Benralizumab for allergic asthma: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Benralizumab induces rapid and near-complete depletion of eosinophils from blood and lung tissue. We investigated whether benralizumab could attenuate the allergen-induced late asthmatic response (LAR) in participants with allergic asthma. METHODS: Participants with allergic asthma who demonstrated increased sputum eosinophils and LAR at screening were randomised to benralizumab 30 mg or matched placebo given every 4 weeks for 8 weeks (3 doses). Allergen challenges were performed at weeks 9 and 12 when blood, sputum, bone marrow and bronchial tissue eosinophils and LAR were assessed. RESULTS: 46 participants (mean age 30.9 years) were randomised to benralizumab (n=23) or placebo (n=23). Eosinophils were significantly reduced in the benralizumab group compared with placebo in blood at 4 weeks and sputum and bone marrow at 9 weeks after treatment initiation. At 7 h after an allergen challenge at week 9, sputum eosinophilia was significantly attenuated in the benralizumab group compared to placebo (least squares mean difference -5.81%, 95% CI -10.69- -0.94%; p=0.021); however, the LAR was not significantly different (least squares mean difference 2.54%, 95% CI 3.05-8.12%; p=0.363). Adverse events were reported for seven (30.4%) and 14 (60.9%) participants in the benralizumab and placebo groups, respectively. CONCLUSION: Benralizumab administration over 8 weeks resulted in a significant attenuation of blood, bone marrow and sputum eosinophilia in participants with mild allergic asthma; however, there was no change in the LAR, suggesting that eosinophils alone are not a key component of allergen-induced bronchoconstriction.

Inhaled anti-TSLP antibody fragment, ecleralimab, blocks responses to allergen in mild asthma.

BACKGROUND: Thymic stromal lymphopoietin (TSLP) is a key upstream regulator driving allergic inflammatory responses. We evaluated the efficacy and safety of ecleralimab, a potent inhaled neutralising antibody fragment against human TSLP, using allergen inhalation challenge (AIC) in subjects with mild atopic asthma. METHODS: This was a 12-week, randomised, double-blind, placebo-controlled, parallel-design, multicentre allergen bronchoprovocation study conducted at 10 centres across Canada and Germany. Subjects aged 18-60 years with stable mild atopic asthma were randomised (1:1) to receive 4 mg once-daily inhaled ecleralimab or placebo. Primary end-points were the allergen-induced change in forced expiratory volume in 1 s (FEV1) during the late asthmatic response (LAR) measured by area under the curve (AUC3-7h) and maximum percentage decrease (LAR%) on day 84, and the safety of ecleralimab. Allergen-induced early asthmatic response (EAR), sputum eosinophils and fractional exhaled nitric oxide (F ENO) were secondary and exploratory end-points. RESULTS: 28 subjects were randomised to ecleralimab (n=15) or placebo (n=13). On day 84, ecleralimab significantly attenuated LAR AUC3-7h by 64% (p=0.008), LAR% by 48% (p=0.029), and allergen-induced sputum eosinophils by 64% at 7 h (p=0.011) and by 52% at 24 h (p=0.047) post-challenge. Ecleralimab also numerically reduced EAR AUC0-2h (p=0.097) and EAR% (p=0.105). F ENO levels were significantly reduced from baseline throughout the study (p<0.05), except at 24 h post-allergen (day 43 and day 85). Overall, ecleralimab was safe and well tolerated. CONCLUSION: Ecleralimab significantly attenuated allergen-induced bronchoconstriction and airway inflammation, and was safe in subjects with mild atopic asthma.

Sounding the alarmins-The role of alarmin cytokines in asthma.

The alarmin cytokines thymic stromal lymphopoietin (TSLP), interleukin (IL)-33, and IL-25 are epithelial cell-derived mediators that contribute to the pathobiology and pathophysiology of asthma. Released from airway epithelial cells exposed to environmental triggers, the alarmins drive airway inflammation through the release of predominantly T2 cytokines from multiple effector cells. The upstream positioning of the alarmins is an attractive pharmacological target to block multiple T2 pathways important in asthma. Blocking the function of TSLP inhibits allergen-induced responses including bronchoconstriction, airway hyperresponsiveness, and inflammation, and subsequent clinical trials of an anti-TSLP monoclonal antibody, tezepelumab, in asthma patients demonstrated improvements in lung function, airway responsiveness, inflammation, and importantly, a reduction in the rate of exacerbations. Notably, these improvements were observed in patients with T2-high and with T2-low asthma. Clinical trials blocking IL-33 and its receptor ST2 have also shown improvements in lung function and exacerbation rates; however, the impact of blocking the IL-33/ST2 axis in T2-high versus T2-low asthma is unclear. To date, there is no evidence that IL-25 blockade is beneficial in asthma. Despite the considerable overlap in the cellular functions of IL-25, IL-33, and TSLP, they appear to have distinct roles in the immunopathology of asthma.

Respiratory System Dynamics.

While static mechanical forces govern resting lung volumes, dynamic forces determine tidal breathing, airflow, and changes in airflow and lung volume during normal and abnormal breathing. This section will examine the mechanisms, measurement methodology, and interpretation of the dynamic changes in airflow and lung volume that occur in health and disease. We will first examine how the total work of breathing can be described by the parameters of the equation of motion, which determine the pressure required to move air into and out of the lung. This will include a detailed description of airflow characteristics and airway resistance. Next, we will review the changes in pressure and flow that determine maximal forced inspiration and expiration, which result in the maximal flow-volume loop and the clinically important forced expired volume in 1 second. We will also assess the mechanisms and interpretation of bronchodilator responsiveness, dynamic hyperinflation, and airways hyperresponsiveness.

Allergen provocation tests in respiratory research: building on 50†years of experience.

The allergen provocation test is an established model of allergic airway diseases, including asthma and allergic rhinitis, allowing the study of allergen-induced changes in respiratory physiology and inflammatory mechanisms in sensitised individuals as well as their associations. In the upper airways, allergen challenge is focused on the clinical and pathophysiological sequelae of the early allergic response, and is applied both as a diagnostic tool and in research settings. In contrast, bronchial allergen challenge has almost exclusively served as a research tool in specialised research settings with a focus on the late asthmatic response and the underlying type 2 inflammation. The allergen-induced late asthmatic response is also characterised by prolonged airway narrowing, increased nonspecific airway hyperresponsiveness and features of airway remodelling including the small airways, and hence allows the study of several key mechanisms and features of asthma. In line with these characteristics, allergen challenge has served as a valued tool to study the cross-talk of the upper and lower airways and in proof-of-mechanism studies of drug development. In recent years, several new insights into respiratory phenotypes and endotypes including the involvement of the upper and small airways, innovative biomarker sampling methods and detection techniques, refined lung function testing as well as targeted treatment options further shaped the applicability of the allergen provocation test in precision medicine. These topics, along with descriptions of subject populations and safety, in line with the updated Global Initiative for Asthma 2021 document, will be addressed in this review.

Effect of daily dosing with tiotropium against methacholine induced bronchoconstriction in asthmatics.

INTRODUCTION: Loss of bronchoprotection against direct and indirect acting stimuli following regular use of inhaled beta2-agonists occurs with both short and long-acting formulations. Comparatively little is known about the development of tolerance following regular use of inhaled muscarinic receptor antagonists. Two investigations with the short-acting muscarinic receptor antagonist ipratropium bromide have reported no tolerance after regular use against inhaled methacholine. To our knowledge, there are no data regarding loss of bronchoprotection following regular use of long-acting muscarinic receptor antagonist. We therefore looked at the effect of daily dosing with tiotropium on methacholine induced bronchoconstriction in a population of mild asthmatics. METHODS: We performed a randomized, double-blind, placebo-controlled cross-over study comparing tiotropium Respimat® 5 µg to placebo in adult asthmatics. Each treatment arm began with baseline methacholine challenge followed immediately by treatment administration. One hour later a post treatment methacholine challenge was performed. Participants dosed daily (two puffs) at home for the next six days and returned to the lab on Day 8 for a final dose of treatment 1 h prior to methacholine challenge. RESULTS: The average doubling dose increase in methacholine PD20 following a single dose of tiotropium was 3.9 doubling doses whereas that following placebo was 0.93 (p = 0.003). After regular use, methacholine PD20 was further increased to 6.4 doubling doses following tiotropium whereas that following placebo decreased by 0.57 doubling doses (p < 0.001). CONCLUSION: LAMA are indicated for use as add-on monotherapy or in triple therapy combination for poorly controlled asthma. It may be reassuring to know therefore, that regular use does not result in loss of bronchoprotection like that which occurs with beta2-agonist bronchodilators.

Muscarinic Receptor Antagonism and Allergen Induced Airway Responses in Allergic Asthma: A Scoping Review.

PURPOSE: The purpose of this scoping review was to identify existing clinical and basic science knowledge surrounding the effect of muscarinic receptor antagonism on allergen-induced airway responses to inform future clinical research in this area. METHODS: Multiple advanced searches were performed using the National Library of Medicine PubMed search engine. Each search began with two terms; for example, "atropine and asthma" or "tiotropium and airway inflammation". Results were then further refined to include terms such as "allergen" or "ovalbumin (OVA)". Abstracts of refined searches were reviewed for relevance to allergic asthma and allergen-induced airway responses including the early and late asthmatic responses, airway inflammation and tissue remodelling. There was no restriction regarding publication date. Reference lists of selected papers were also reviewed for relevant publications. RESULTS: Nine human clinical trial publications and fourteen animal model publications were identified. In humans, single dose atropine (n=4), ipratropium (n=4) or oxitropium (n=1) administered pre-challenge produced equivocal effects on allergen-induced early asthmatic responses as reported but favored inhibition in eight of nine studies after re-analyses. Animal model investigations (n=14) showed mostly favorable results, especially with respect to airway inflammation and tissue remodelling, although two studies were negative, and one study showed a worsening in allergen induced airway inflammation following muscarinic receptor antagonism. CONCLUSION: Existing human and animal model data suggest muscarinic receptor antagonism may be beneficial in preventing allergen induced airway responses in those with allergic asthma. Additional human research utilizing current standardized methodologies is required.

Direct and indirect bronchoprovocation tests in dose-response studies of inhaled corticosteroids: Past, present, and future directions.

Inhaled corticosteroids (ICS) are a mainstay of treatment in eosinophilic asthma. Many studies have explored the dose-response effect of different formulations of ICS through direct or indirect bronchoprovocation testing. Such studies are important for investigating efficacy and identifying the relative potency between formulations. However, lack of consistency in methods and designs has hindered the comparability of study findings. This review discusses current knowledge of the dose-response, or lack thereof, of different formulations of ICS through direct and indirect bronchoprovocation testing. The strengths and weaknesses of past studies inform recommendations for future methodological considerations in this field, such as utilizing a randomized double-blind crossover design, enrolling participants likely to respond to ICS therapy, and carefully selecting treatment durations and washout periods to assess incremental improvement in airway hyperresponsiveness while reducing the likelihood of a carryover effect.

Assessment Of Ratio Of Peak Expiratory Flow Rate To Vital Capacity For Identifying Pulmonary Fibrosis.

BACKGROUND: Pulmonary fibrosis (PF) is associated with reduction in vital capacity (VC) and increase in expiratory flow rates, including peak expiratory flow (PEF). Full pulmonary function testing and computed tomography chest scans are limited resources in some geographic areas and a simple and sensitive screening test would be of value. We hypothesized that increase in the ratio of % predicted PEF over % predicted VC (%PEF/%VC), from spirometry alone might be sensitive to screen for pulmonary fibrosis. METHODS: The %PEF/%VC from 1,000 consecutive spirometric flow volume curves was nearly normally distributed: 7.5% (approximately 1.5 standard deviations) had a ratio ≥ 1.4. We evaluated the sensitivity and specificity of this cut point for a diagnosis of PF in a retrospective chart review of 391 patients with good quality spirometry and respirologists' confirmed diagnoses. RESULTS: Of the 391 patients analyzed, 98 had PF, 79 were normal, 70 had a combined obstructive and restrictive processes, 57 had obstructive lung disease, 61 had extra-parenchymal restriction and 26 had non-fibrotic interstitial lung disease. A %PEF/%VC ≥ 1.4 was only 54.1% sensitive in predicting PF, however it had a specificity of 94.9%. There was a 95.1% specificity for ruling in intra-parenchymal opposed to extra-parenchymal restriction. CONCLUSION: A %PEF/%VC ≥ 1.4 was not sensitive enough to screen for PF but did demonstrate high specificity and thus may be helpful in identifying intraparenchymal restriction.

The effect of deep inhalation on mannitol responsiveness.

BACKGROUND: Mannitol inhalation testing is specific for asthmatics with eosinophilic airway inflammation, a factor that has been negatively correlated with the development of deep inhalation bronchoprotection. OBJECTIVE: To evaluate the effect of deep inhalations on responsiveness to inhaled mannitol in correlation with the degree of airway inflammation. METHODS: Twenty participants with stable asthma completed this randomized, crossover study. A screening visit assessed responsiveness to methacholine and airway inflammation through fractional exhaled nitric oxide (FeNO) measures and sputum induction. Participants next completed two mannitol challenges, one with deep inhalations (standard method) and one with inhalations to half of total lung capacity, and two methacholine challenges, one with tidal breathing (standard method) and one with deep inhalations. Only the inhalation technique for dose administration differed between repeat mannitol or methacholine challenges. RESULTS: Deep inhalations did not significantly influence the provocative dose of mannitol causing a 15% fall in forced expiratory volume in 1 second ((P = .73; n = 7) or the mannitol dose-response slope (P = .26; n = 20). Deep inhalations produced significant bronchoprotection against methacholine (P = .03; n = 20). FeNO levels were significantly correlated to sputum eosinophilia (P = .02; n = 15), responsiveness to deep inhalation methacholine (P = .005; n = 20), the dose-response slopes from deep inhalation mannitol (P = .01; n = 20), and the dose-response slope from non-deep inhalation mannitol (P = .005; n = 20). CONCLUSIONS AND CLINICAL RELEVANCE: Deep inhalations did not produce significant bronchoprotection against inhaled mannitol. This result is in agreement with past findings linking airway inflammation with loss of deep inhalation bronchoprotection. CLINICAL TRIAL REGISTRATION: This study was prospectively registered on clinicaltrials.gov (NCT03505489).

ERS technical standard on bronchial challenge testing: pathophysiology and methodology of indirect airway challenge testing.

Recently, this international task force reported the general considerations for bronchial challenge testing and the performance of the methacholine challenge test, a "direct" airway challenge test. Here, the task force provides an updated description of the pathophysiology and the methods to conduct indirect challenge tests. Because indirect challenge tests trigger airway narrowing through the activation of endogenous pathways that are involved in asthma, indirect challenge tests tend to be specific for asthma and reveal much about the biology of asthma, but may be less sensitive than direct tests for the detection of airway hyperresponsiveness. We provide recommendations for the conduct and interpretation of hyperpnoea challenge tests such as dry air exercise challenge and eucapnic voluntary hyperpnoea that provide a single strong stimulus for airway narrowing. This technical standard expands the recommendations to additional indirect tests such as hypertonic saline, mannitol and adenosine challenge that are incremental tests, but still retain characteristics of other indirect challenges. Assessment of airway hyperresponsiveness, with direct and indirect tests, are valuable tools to understand and to monitor airway function and to characterise the underlying asthma phenotype to guide therapy. The tests should be interpreted within the context of the clinical features of asthma.

Bronchoprotective effect of vilanterol against methacholine-induced bronchoconstriction in mild asthmatics: A randomized three-way crossover study.

BACKGROUND: Ultra-long-acting ß2 agonists (uLABA) are relatively new anti-asthma medications of which there are three different formulations currently available: olodaterol, indacaterol, and vilanterol. The first 2 formulations have been shown to exert bronchoprotective effects; they are able to prevent airway smooth muscle contraction on exposure to constricting stimuli. However, studies have found that these 2 drugs produce different degrees and durations of bronchoprotection against methacholine. OBJECTIVE: The objective of this study was to investigate the degree of bronchoprotection provided by vilanterol against methacholine-induced bronchoconstriction. METHODS: Fourteen patients with mild-to-moderate asthma (8 male; baseline percent predicted forced expiratory volume in 1 second [FEV1] > 65%; provocative concentration of methacholine causing a 20% reduction in FEV1 [PC20] ≤ 8 mg/mL) completed this randomized, double-blind, 3-way crossover study. Methacholine challenges were performed before treatment administration (placebo, 100 µg fluticasone furoate, or 25 µg vilanterol + 100 µg fluticasone furoate) and at 0.5 and 24 hours posttreatment. Each treatment arm was separated by a minimum 7-day washout period. A combination therapy of vilanterol+fluticasone furoate was used, because vilanterol is not available as a monotherapy. RESULTS: Significant bronchoprotection was evident after the combination treatment at both 0.5 and 24 hours with doubling dose shifts in methacholine PC20 of 2.0 (P = .0004) and 1.6 (P = .0001), respectively. Clinically significant bronchodilation was only recorded at 24 hours after combination treatment (P < .05). CONCLUSION: These findings suggest that vilanterol (in combination with fluticasone furoate) provides significant bronchoprotection against methacholine-induced bronchoconstriction for at least 24 hours in patients with mild-to-moderate asthma. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov (NCT03315000).

Environmental Causes of Asthma.

Environmental factors which cause asthma are those that induce airway inflammation with eosinophils (more common) or neutrophils along with airway hyperresponsiveness (AHR). The most common of these (indeed the most common cause of asthma) are IgE-mediated inhalant allergen exposures. Allergen-induced AHR and inflammation are both associated with the allergen-induced late asthmatic response (LAR). Although allergens were previously recognized only as causes of symptoms and bronchoconstriction in asthmatics, we now appreciate them as causes of the fundamental pathophysiologic features of asthma. Low-molecular-weight chemical sensitizers, causes of occupational asthma, also cause asthma in a manner analogous to allergen. Acute irritant-induced asthma (reactive airways dysfunction syndrome) following a very heavy irritant exposure and chronic irritant-induced asthma following repeated high exposures can also induce persistent or permanent changes (inflammation and AHR) consistent with asthma. Textile dust exposure produces a different form of airway disease (byssinosis) which is less frequently observed currently. Environmental exposure to tobacco smoke facilitates the development of asthma in children. Personal smoking and environmental air pollution have an inconsistent and likely generally small effect in causing asthma.

ERS technical standard on bronchial challenge testing: general considerations and performance of methacholine challenge tests.

This international task force report updates general considerations for bronchial challenge testing and the performance of the methacholine challenge test. There are notable changes from prior recommendations in order to accommodate newer delivery devices. Rather than basing the test result upon a methacholine concentration (provocative concentration (PC20) causing a 20% fall in forced expiratory volume in 1 s (FEV1)), the new recommendations base the result upon the delivered dose of methacholine causing a 20% fall in FEV1 (provocative dose (PD20)). This end-point allows comparable results from different devices or protocols, thus any suitable nebuliser or dosimeter may be used, so long as the delivery characteristics are known. Inhalation may be by tidal breathing using a breath-actuated or continuous nebuliser for 1 min (or more), or by a dosimeter with a suitable breath count. Tests requiring maximal inhalations to total lung capacity are not recommended because the bronchoprotective effect of a deep breath reduces the sensitivity of the test.

The effect of glycopyrronium and indacaterol, as monotherapy and in combination, on the methacholine dose-response curve of mild asthmatics: a randomized three-way crossover study.

BACKGROUND: Methacholine dose-response curves illustrate pharmacologic bronchoprotection against methacholine-induced airway hyperresponsiveness and can be used to quantitate changes in airway sensitivity (position), reactivity (slope), and maximal responsiveness following drug administration. Our objective was to determine the influence of single-dose glycopyrronium (long-acting muscarinic antagonist) and indacaterol (ultra-long acting ß2 agonist), as monotherapy and in combination, on the methacholine dose-response curve of mild asthmatics and to compare these findings with a non-asthmatic control curve. METHODS: This was a randomized, double blind, double dummy, three-way crossover study. For asthmatic participants (n = 14), each treatment arm included a baseline methacholine challenge, drug administration, and repeat methacholine challenges at 1, 24, and 48 h. Non-asthmatic control participants (n = 15) underwent a single methacholine challenge and did not receive any study treatment. Methacholine dose-response curves were graphed as the percent fall in forced expiratory volume in 1 s (FEV1) for each methacholine concentration administered. Best-fit curves were then generated. Differences in airway reactivity were calculated through linear regression. Changes in airway sensitivity were assessed as the shift in the provocative concentration of methacholine causing a 20% fall in FEV1. RESULTS: Compared to baseline, all treatments significantly reduced airway sensitivity to methacholine at 1 h post-dose (indacaterol ~1.5 doubling concentrations; glycopyrronium ~5 doubling concentrations; combination ~5 doubling concentrations). Bronchoprotection at 24 and 48 h remained significant with glycopyrronium and combination therapy only. Airway reactivity was not influenced by indacaterol whereas glycopyrronium significantly reduced airway reactivity at all time-points (p = 0.003-0.027). The combination significantly decreased slope at 1 (p = 0.021) and 24 (p = 0.039) hours only. The non-asthmatic control and 1-h glycopyrronium curves are nearly identical. Only the non-asthmatic control and 1-h post-combination therapy curves appeared to generate a true response plateau (three data points within 5%), which occurred at a 14% fall in FEV1. CONCLUSIONS: Methacholine dose-response curves differentiate the bronchoprotective mechanisms triggered by different classes of asthma medications. Assessment of bronchoprotection using methacholine dose-response curves may be useful during clinical development of respiratory medications when performing superiority, equivalence, or non-inferiority trials. TRIAL REGISTRATION: clinicaltrials.gov ( NCT02953041 ). Retrospectively registered on October 24th 2016.

Efficacy and safety of multiple doses of QGE031 (ligelizumab) versus omalizumab and placebo in inhibiting allergen-induced early asthmatic responses.

BACKGROUND: Omalizumab is an established anti-IgE therapy for the treatment of allergic diseases that prevents IgE from binding to its receptor. QGE031 is an investigational anti-IgE antibody that binds IgE with higher affinity than omalizumab. OBJECTIVE: This study compared the effects of QGE031 with those of omalizumab on clinical efficacy, IgE levels, and FcεRI expression in a clinical model of allergic asthma. METHODS: Thirty-seven patients with mild allergic asthma were randomized to subcutaneous omalizumab, placebo, or QGE031 at 24, 72, or 240 mg every 2 weeks for 10 weeks in a double-blind, parallel-group multicenter study. Inhaled allergen challenges and skin tests were conducted before dosing and at weeks 6, 12, and 18, and blood was collected until 24 weeks after the first dose. RESULTS: QGE031 elicited a concentration- and time-dependent change in the provocative concentration of allergen causing a 15% decrease in FEV1 (allergen PC15) that was maximal and approximately 3-fold greater than that of omalizumab (P = .10) and 16-fold greater than that of placebo (P = .0001) at week 12 in the 240-mg cohort. Skin responses reached 85% suppression at week 12 in the 240-mg cohort and were maximal at week 18. The top doses of QGE031 consistently suppressed skin test responses among subjects but had a variable effect on allergen PC15 (2-fold to 500-fold change). QGE031 was well tolerated. CONCLUSION: QGE031 has greater efficacy than omalizumab on inhaled and skin allergen responses in patients with mild allergic asthma. These data support the clinical development of QGE031 as a treatment of asthma.

Lung function and respiratory symptoms in a randomized smoking cessation trial of electronic cigarettes.

Quitting smoking is the most important step smokers can take to improve their health. Nonetheless, there is little information on long-term improvements in lung function and/or respiratory symptoms after smoking cessation. Here we illustrate long-term changes in spirometric indices as well as in respiratory symptoms in smokers invited to quit or reduce their cigarette consumption by switching to electronic cigarettes (ECs). Prospective evaluation of cigarette consumption, spirometry and symptoms was performed in a 1-year randomized controlled trial of smokers receiving EC containing 2.4%, 1.8% or 0% nicotine. Spirometric data are presented on the basis of participants' pooled continuous smoking phenotype classification (Quitters, Reducers, Failures), whereas respiratory symptoms on the basis of their point prevalence-smoking phenotype. Smoking phenotype classification (Quitters, Reducers, Failures) had no significant effect on spirometric indices (FEV1, FVC and FEV1/FVC) with the exception of FEF25-75%, which significantly (P =0.034) increased over the time among Quitters; their FEF25-75% (% predicted) improving from (means±S.D.) 85.7±15.6% at baseline (BL) to 100.8±14.6%. High prevalence of cough/phlegm (43.1%) and shortness of breath (SoB; 34.8%) was reported at BL with substantial reduction in their frequency at subsequent follow-up visits. These symptoms virtually disappeared very quickly in both quitters and reducers. Smokers invited to switch to ECs who completely abstained from smoking showed steady progressive improvements in their FEF25-75% Normalization of peripheral airways function was associated with improvement in respiratory symptoms, adding to the notion that abstaining from smoking can reverse tobacco harm in the lung.