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Highlights • Particulate matter air pollution is common in military deployment environments of Iraq and Afghanistan. • Respiratory symptoms are frequently reported post-deployment, yet spirometry is frequently preserved. • Using the forced oscillation technique (FOT), 75% of veterans with preserved spirometry had distal airway dysfunction. • Veterans with distal airway dysfunction may represent at an at-risk population requiring closer surveillance. Abstract Purpose To evaluate the utility of the forced oscillation technique (FOT) among military veterans with preserved spirometry and chronic unexplained respiratory symptoms. Methods 178 veterans referred for evaluation of unexplained respiratory symptoms completed pulmonary function testing and FOT. Preserved spirometry was defined as FEV 1 /FVC, FEV 1 and FVC ≥ 5th percentile. Frequency dependence of resistance (R4-R20) and reactance area (AX) were assessed via FOT, and R4-R20 ≥ 20% and AX ≥ 95th percentile were considered abnormal. Results Spirometry was preserved in 71.3%, of whom 124 had acceptable FOT data. 93 of 124 (75.0%) veterans with preserved spirometry had one or more abnormal findings on FOT. Veterans with abnormal R4-R20 and/or AX had reduced FVC, FEV 1 , FEF 25-75 , and diffusing capacity (% predicted) in comparison to those with Normal FOT (p = 0.030 to p < 0.001). Conclusions In our referral sample, distal airway dysfunction in the presence of preserved spirometry appears common and may represent an at-risk group requiring closer surveillance. [ABSTRACT FROM AUTHOR]

We report here the establishment and characterization of an in vitro human small airway model (SmallAir™). The epithelial cells were isolated from the distal lungs by enzymatic digestion. After amplification, the cells were seeded on the microporous membrane of Transwell inserts. Once confluent, the cultures were switched to air-liquid interface. After 3 weeks of culture, the epithelium became fully differentiated, with morphology of columnar epithelium, and a thickness of 10–15 μm. Most significantly, CC-10, a specific marker of Club cells, was highly expressed in SmallAir™. CC-10 was detected by both immune-cytochemistry and Western Blot. As expected, SmallAir™ contained few Muc5-Ac positive cells (goblet cells). In contrast, CC-10 was not detected in MucilAir™, an in vitro model of the human nasal and bronchial epithelial model. Instead, Muc5-Ac was highly expressed in MucilAir™. However, both MucilAir™ and SmallAir™ contain basal cells and ciliated cells, showing cilia beating and mucociliary clearance. Clearly, MucilAir™ and SmallAir™ are two distinct airway epithelial models. [ABSTRACT FROM AUTHOR]

Inhalation of diacetyl-containing products is associated with risk for occupational bronchiolitis obliterans (BO) and fixed airways obstruction, particularly in workers exposed to heated liquids and powdered formulations. This review describes the occupational settings in which diacetyl-related lung disease has been reported and the clinical presentation of disease, along with an approach to diagnosis and management. The importance of early disease recognition, appropriate removal from exposure, and medical monitoring to optimize prognosis is reviewed. The roles of public health follow-up and medical surveillance for primary and secondary prevention are discussed. [ABSTRACT FROM AUTHOR]

Background The multiple-breath inert gas washout parameter acinar ventilation heterogeneity (S acin ) is thought to be a marker of acinar airway involvement but has not been validated by using quantitative imaging techniques in asthmatic patients. Objective We aimed to use hyperpolarized 3 He diffusion magnetic resonance at multiple diffusion timescales and quantitative computed tomographic (CT) densitometry to determine the nature of acinar airway involvement in asthmatic patients. Methods Thirty-seven patients with asthma and 17 age-matched healthy control subjects underwent spirometry, body plethysmography, multiple-breath inert gas washout (with the tracer gas sulfur hexafluoride), and hyperpolarized 3 He diffusion magnetic resonance. A subset of asthmatic patients (n = 27) underwent quantitative CT densitometry. Results Ninety-four percent (16/17) of patients with an increased S acin had Global Initiative for Asthma treatment step 4 to 5 asthma, and 13 of 17 had refractory disease. The apparent diffusion coefficient (ADC) of 3 He at 1 second was significantly higher in patients with S acin -high asthma compared with that in healthy control subjects (0.024 vs 0.017, P < .05). S acin correlated strongly with ADCs at 1 second ( R = 0.65, P < .001) but weakly with ADCs at 13 ms ( R = 0.38, P < .05). ADCs at both 13 ms and 1 second correlated strongly with the mean lung density expiratory/inspiratory ratio, a CT marker of expiratory air trapping ( R = 0.77, P < .0001 for ADCs at 13 ms; R = 0.72, P < .001 for ADCs at 1 second). Conclusion S acin is associated with alterations in long-range diffusion within the acinar airways and gas trapping. The precise anatomic nature and mechanistic role in patients with severe asthma requires further evaluation. [ABSTRACT FROM AUTHOR]

To evaluate the regional delivery of conventional aerosol medications, a new whole-lung computational fluid dynamics modeling approach was applied for metered dose inhaler (MDI) and dry powder inhaler (DPI) aerosols delivered to healthy and constricted airways. The computational fluid dynamics approach included complete airways through the third respiratory bifurcation (B3) and applied the new stochastic individual pathway modeling technique beyond B3 through the remainder of the conducting airways together with a new model of deposition in the alveolar region. Bronchiolar (B8-B15) deposition fraction values were low (∼1%) for both MDI and DPI aerosols with the healthy geometry, whereas delivery to the constricted model was even lower, with deposition fraction values of 0.89% and 0.81% for the MDI and DPI, respectively. Calculating dose per unit surface area for the commercial MDI and DPI products resulted in approximately 10 −3 μg/cm 2 in the lower tracheobronchial region of B8-B15 and 10 −4 μg/cm 2 in the alveolar region. Across the lung, dose per unit surface area varied by 2 orders of magnitude, which increased to 4 orders of magnitude when the mouth-throat region was included. The MDI and DPI both provided very low drug dose per unit surface area to the small tracheobronchial and alveolar airways. [ABSTRACT FROM AUTHOR]

Respiratory tract lining fluid (RTLF) is an important component of the lung epithelial barrier. Pathological changes in RTLF may cause increased permeability of the epithelial barrier, but changes within RTLF are difficult to assess non-invasively. The aim of this study was to explore if the use of the non-invasive measurement technique, Particles in Exhaled Air (PEx) and blood test were useful in assessing epithelial barrier, and if cigarette smoking affects the relationship. In a general population subcohort from the European Community Respiratory Health Survey III in Iceland (n = 112), we collected RTLF droplets using the PEx technique, in conjunction with blood samples and questionnaire data. We measured surfactant protein A (SP-A) in the collected plasma and PEx samples. Participants were defined as healthy if they did not currently have asthma, were non-smokers and had forced expiratory volume in one second ≥ 80% of predicted value. Of the 112 participants, 97 were healthy and 15 were current smokers. There was no correlation between plasma and PEx SP-A levels. However, the ratio of plasma to PEx SP-A was significantly higher in smokers compared to healthy subjects. The lack of correlation between PEx and plasma SP-A in healthy participants, indicates that SP-A in plasma does not diffuse freely over the lung epithelial barrier. However, the lung epithelial barrier may be injured by smoking, leading to diffusion of SP-A across the barrier into the bloodstream, causing an increased ratio of plasma to PEx SP-A. • Particles in Exhaled Air, PExA. • Lung barrier function. • Surfactant Protein A. • Lung epithelium. • Changes in surfactant in disease. [ABSTRACT FROM AUTHOR]

Highlights: [•] We assessed from resistance/reactance values the individual response to methacholine test. [•] For PD20>200μg, poor frequency dependence suggests homogeneous bronchoconstriction. [•] For PD20<200μg high frequency dependence suggests responsiveness of the distal airways. [Copyright &y& Elsevier]

Pseudomonas aeruginosa (P. aeruginosa) is commonly isolated from the sputum of COPD patients. However, the precise role of P. aeruginosa infection in the progression of COPD, especially its role in altering inflammation remains unclear. Here, we designed mice models of COPD infected with P. aeruginosa (PA) and observed dynamic changes of lung structure, lung inflammatory microenvironment, lung function. After infection, the level of mucus secretion peaked on day 3 and remained higher throughout the study period, and the airway remodeling and emphysema was starkly apparent on day 14 and 21. On day 3, interferon-γ and interleukin (IL)− 5 levels increased rapidly, accompanied by elevated T-bet mRNA expression and CD4+T-bet+ cells; at the late stage of infection (days 14 and 21), consistent with increased GATA3 mRNA expression and CD4+GATA3+ cells, IL-4 and IL-13 levels significantly increased; IL-17A level, Foxp3 mRNA expression, CD4 + ROR-γt + cells and CD4 + FOXP3 + cells remained at higher levels throughout the course of the infection. Small-airway function showed a decline from day 3 to day 21; large airway function showed a decline on day 14 and 21. Overall, P. aeruginosa infection contributed to the progression of COPD. During the infection, an early Th1-related inflammation gradually shifted to a later Th2-related inflammation, and small-airway function decline occurred earlier than that of large-airway function. On the basis of infection control, the appropriate use of glucocorticoid might slow disease progression by mitigating the enhanced Th2-related inflammation, and small airways could be also an important treatment target in P. aeruginosa -infected COPD patients. [Display omitted] • P. aeruginosa infection worsened lung function, airway remodeling, mucus secretion, pulmonary inflammation, and emphysema in the context of COPD. • During the P. aeruginosa infection, an early Th1-related inflammation gradually shifted to a later Th2-related inflammation in COPD mouse models. • During the P. aeruginosa infection, small-airway function decline occurred earlier than that of large-airway function in COPD mouse models. [ABSTRACT FROM AUTHOR]

Asthma is a disease characterized by inflammation which affects both proximal and distal airways. We evaluated the prevalence of small airway obstruction (SAO) in a group of clinically stable asthmatics with both normal forced expiratory volume in the first second (FEV1) and normal FEV1/forced vital capacity (FVC) and treated with an association of inhaled corticosteroids (ICSs) and long acting β2-agonists (LABAs). Clinical evaluation included the measurement of dyspnea, asthma control test and drug compliance. The prevalence of SAO was estimated by spirometry and plethysmography and defined by the presence of one or more of the following criteria: functional residual capacity (FRC) > 120% predicted (pred), residual volume (RV) > pred + 1.64 residual standard deviation (RSD), RV/total lung capacity (TLC) > pred + 1.64 RSD, forced expiratory flow (FEF)25-75% < pred - 1.64 RSD, FEF50% < pred - 1.64 RSD, slow vital capacity (SVC) - FVC > 10%. Among the 441 patients who were included, 222 had normal FEV1 and FEV1/FVC. At least one criteria of SAO was found in 115 (52%) mainly lung hyperinflation (39% based on high FRC, RV or RV/TLC) and more rarely distal airflow limitation (15% based on FEF25-75% or FEF50%) or expiratory trapping (10% based on increased SVC - FVC). In the patients with only SAO (no PAO), there was no relationship between SAO, asthma history and the scores of dyspnea, asthma control or drug compliance. These results suggest that in asthmatics with normal FEV1 and FEV1/FVC, treated with ICSs and LABAs, SAO is found in more than half of the patients indicating that the routinely used lung function tests can underestimate dysfunctions occurring in the small airways. [ABSTRACT FROM AUTHOR]

Highlights: [•] Halothane is amore potent bronchodilator of the small airways than isoflurane. [•] We evaluated if intranasal challenge under halothane vs. isoflurane anesthesia would lead to an enhanced allergic response. [•] Peripheral lung inflammation was significantly increased in halothane compared to isoflurane OA-challenged mice. [•] Airway challenge under halothane induces a higher level of airway hyperresponsiveness than under isoflurane anesthesia. [•] Intranasal challenges under different anesthesia support the importance of the small airways in asthma pathogenesis. [ABSTRACT FROM AUTHOR]

Background: The role of the peripheral airways in asthma is increasingly being recognized as a potential target for the achievement of optimal control of the disease. We postulated that the inflammatory changes of the small airways are implicated in the lack of asthma control in mild asthma. Objective: To test this hypothesis, we measured the alveolar fraction of exhaled NO (CalvNO) in patients with mild asthma with different levels of control of symptoms. Methods: Seventy-eight patients with asthma (35 men, age, 37 ± 15 years; FEV1 percentage of predicted, 100% ± 9%) were studied. Asthma control was assessed by using the Asthma Control Test (ACT). Measurements of exhaled NO at multiple constant flows were performed. Results: Bronchial NO concentrations were 27.1 ± 20 ppb, and CalvNO levels were 5.7 ± 3.4 ppb. The ACT score was 20 ± 4.2. The level of asthma control was not associated with bronchial NO concentrations (r s = 0.16, P = .15). However, a significant correlation was found between the ACT score and CalvNO (r s = 0.25, P = .03). Moreover, CalvNO was significantly higher in patients with uncontrolled asthma than in patients with controlled/partially controlled asthma (6.7 ± 2.6 ppb vs 4.9 ± 2.6 ppb, respectively, P = .02). In the subgroup of patients with asthma who underwent extrafine inhaled corticosteroid treatment, the magnitude of the inhaled corticosteroid–induced improvement in asthma control positively correlated with baseline CalvNO at 1 month (r s = 0.39, P = .003) and at 3 months (r s = 0.49, P < .0001). Conclusions: The alveolar component of exhaled NO is associated with the lack of asthma control in patients with mild, untreated asthma. This observation supports the notion that abnormalities of the peripheral airways are implicated in the mildest forms of asthma. [Copyright &y& Elsevier]

Background: Asthma guidelines recommend inhaled corticosteroid (ICS) dose titration for patients on the basis of an assessment of current asthma control. However, the physiological determinants of asthma symptom control are poorly understood and spirometry is a poor predictor of symptomatic response. Objective: To determine the role of small airway measurements in predicting the symptom response following ICS dose titration. Methods: Adult asthmatic patients had the Asthma Control Questionnaire (ACQ) scores and lung function measured at baseline and after 8 weeks. Tests included spirometry, plethysmography, sputum cell count, exhaled nitric oxide, airway hyperresponsiveness to mannitol, respiratory system mechanics using the forced oscillation technique, and ventilation heterogeneity using the multiple breath nitrogen washout. The parameters ventilation heterogeneity in convection-dependent airways and ventilation heterogeneity in diffusion-dependent airways were derived as measures of ventilation heterogeneity in the small airways. The dose of ICS was doubled if the ACQ score was greater than or equal to 1.5 (uptitration) and quartered if the ACQ score was less than 1.5 (downtitration). The relationships between baseline physiological parameters and the change in the symptom-only 5-item ACQ (deltaACQ-5) were examined by using Spearman correlations, forward stepwise linear regressions, and receiver operator curve analyses. Results: ICS dose uptitration (n = 20) improved ACQ-5 scores (1.76 to 1.16; P = .04). Baseline fraction of exhaled nitric oxide (r = −0.55; P = .01) and ventilation heterogeneity in convection-dependent airways (r = −0.64; P = .002) correlated with deltaACQ-5, but ventilation heterogeneity in convection-dependent airways was the only independent predictor (r 2 = 0.34; P = 0.007). ICS dose downtitration (n = 41) worsened ACQ-5 scores (0.46 to 0.80; P < .001), with 29% of the patients having a deltaACQ-5 of greater than 0.5. Only baseline ventilation heterogeneity in diffusion-dependent airways correlated with deltaACQ-5 (r = 0.40; P = .009) and identified subjects with deltaACQ-5 of greater than 0.5 (receiver operator curve area under the curve = 0.78; P = .0003). Conclusions: Ventilation heterogeneity predicts symptomatic responses to ICS dose titration. Worse small airways function predicts symptomatic improvement to ICS dose uptitration and loss of symptom control during downtitration. [Copyright &y& Elsevier]

Background: Pentosidine is well established as an intermolecular cross-linking type of advanced glycation end products, and it accumulates with aging in various connective tissues. Objective: To determine whether pentosidine contributes to age-related and disease-related impairment of pulmonary functions in patients with asthma. Methods: We measured pentosidine levels in induced sputum from young to elderly patients with asthma and assessed the slope of the nitrogen (N2) alveolar plateau (delta N2), closing volume (CV), and closing capacity (CC) from a nitrogen washout curve in a single breath. Results: Pentosidine levels in induced sputum were significantly higher in patients with asthma than in normal controls (patients with asthma: median, 20.1, interquartile range, 16.7-26.5 ng/mL; normal controls: median, 3.0, interquartile range, 0.7-7.5 ng/mL; P < .001). The levels were closely correlated with age in both normal controls and patients with asthma. However, the slope of age-related increase in pentosidine levels was markedly steeper in patients with asthma than in normal controls. CV/vital capacity, CC/total lung capacity, and delta N2 increased with aging in both normal controls and patients with asthma. Moreover, in each range of age (21-40, 41-60, 61-80 years), CV/vital capacity, CC/total lung capacity, and delta N2 were significantly higher in patients with asthma than in normal controls. In addition, pentosidine levels in patients with asthma were closely correlated with each of these variables. Conclusion: Our results demonstrated the association between sputum levels of pentosidine and age-related small airways function in both normal controls and patients with asthma. Moreover, the age-related increase in pentosidine levels was more pronounced in patients with asthma. These findings will herald new era in the pathophysiology of elderly asthma. [ABSTRACT FROM AUTHOR]

Background: An important role for exhaled nitric oxide (NO) measurement could be in the distinction between proximal and peripheral lung contributions to inflammation, with a particular interest for the alveolar lung zone and its implication on airway function. Objective: We aimed to isolate the acinar lung zone contribution to both inflammation and airway function to seek a relationship between them. Methods: In 30 patients with asthma with an asthma control test score exceeding 20, indices of conductive and acinar ventilation heterogeneity (Scond, Sacin) were obtained from a multiple breath washout. NO production in the conductive airways (J''awNO), alveolar NO concentration (CANO), and the standard exhaled NO at 50 mL/s (FENO50) were obtained from exhaled NO. Results: Scond was consistently abnormal in all patients with stable asthma, but without any correlation to inflammation abnormality in that compartment (J''awNO). Sacin was particularly abnormal in the asthma subgroup receiving >500 μg budesonide equivalent, and a correlation was found between Sacin and CANO (r = 0.61; P = .015); in this subgroup, a weak association was found between Scond and J''awNO or FENO50 (r = 0.50; P = .059 for both). Conclusion: The persistent functional abnormality of small conductive airways in patients with stable asthma is largely independent of inflammation as measured by exhaled NO. In the alveolar compartment, a functional correlate of alveolar NO was found in a subgroup of patients with stable asthma on moderate-to-high maintenance doses of inhaled steroids. These patients in particular could benefit from novel therapies specifically aimed at improving airway functionality at the level of the acinar entrance and beyond. [Copyright &y& Elsevier]

Summary: In the last few years there has been a growing interest in lung clearance index (LCI), a measure of lung physiology derived from multiple breath washout tests. This resurgence of interest was initially driven by the recognition that such assessments were capable of detecting early airways disease in children, and are more sensitive and easier to perform in this population than conventional lung function tests [Aurora P, Kozlowska W, Stocks J. Gas mixing efficiency from birth to adulthood measured by multiple-breath washout. Respir Physiol Neurobiol, 2005;148(1–2):125–39]. With an appreciation of the importance of earlier identification of airways dysfunction, and prevention of irreversible structural airway changes, methods of following airways disease in these “silent years” are especially important. LCI has now been reported in studies involving all age groups, from infants to adults [Lum S, Gustafsson P, Ljungberg H, Hulskamp G, Bush A, Carr SB, et al. Early detection of cystic fibrosis lung disease: multiple-breath washout versus raised volume tests. Thorax, 2007;62(4):341–7; Horsley AR, Gustafsson PM, Macleod K, Saunders CJ, Greening AP, Porteous D, et al. Lung clearance index is a sensitive, repeatable and practical measure of airways disease in adults with cystic fibrosis. Thorax, 2008;63:135–40], and has a narrow range of normal over this wide age range, making it especially suitable for long-term follow-up studies. In cystic fibrosis (CF) particularly, there is a pressing need for sensitive and repeatable clinical endpoints for therapeutic interventions [Rosenfeld M. An overview of endpoints for cystic fibrosis clinical trials: one size does not fit all. Proc Am Thorac Soc, 2007;4(4):299–301], and LCI has been proposed as an outcome measure in future CF gene therapy studies [Davies JC, Cunningham S, Alton EW, Innes JA. Lung clearance index in CF: a sensitive marker of lung disease severity. Thorax, 2008;63(2):96–7]. This review will consider how LCI is derived, how it differs from conventional lung function testing, and its applications and limitations. [Copyright &y& Elsevier]

Summary: Background: Inhaled corticosteroid therapy suppresses nitric oxide levels (NO) of airway origin but not necessarily NO of alveolar or small airway origin. Systemic therapy with an oral anti-leukotriene agent may suppress NO production in distal airways and alveoli not reached by inhaled therapy. Methods: Adult patients with mild asthma were treated for 3 weeks with inhaled fluticasone 250μg twice daily then with inhaled fluticasone plus oral montelukast 10mg daily for 3 additional weeks. We monitored exhaled NO (eNO), spirometry, lung volumes, and asthma symptoms scores at baseline and at the end of each treatment period. In a subset of patients, we continued with montelukast monotherapy and repeated these measurements. Results: In the 18 patients studied, pulmonary function parameters and asthma symptom scores were not altered significantly from baseline by any therapy. The total eNO at baseline was 55±35.3ppb, dropping to 28.1±15.3ppb (p =0.005) after 3 weeks of fluticasone and to 23.5±14ppb (p =0.001 vs. baseline) after the addition of montelukast. The trend towards reduced total eNO with the combination therapy vs. monotherapy was not statistically significant. Alveolar eNO dropped from 4.2±2.4 at baseline to 3.0±1.5 (p =0.1) after fluticasone and then to 2.2±0.9 (p =0.08 vs. baseline) after fluticasone plus montelukast, increasing then to 3.8±1.8 after montelukast alone (p =0.6 vs. baseline). Conclusions: Leukotriene receptor antagonists administered systemically might decrease small airway/alveolar sites of inflammation when combined to inhaled corticosteroid therapy. [Copyright &y& Elsevier]

Summary: Cigarette smoking causes inflammatory responses in the airways. However, not all smokers exhibit the development of airflow limitation. This study was designed to determine the implications of small airways inflammation in the development of airflow limitation in smokers by our newly explored method. Twenty-eight smokers (15 smokers without airflow limitation and 13 with airflow limitation) were included in this study. Levels of interleukin-8 (IL-8) and 8-isoprostane were measured in epithelial lining fluid (ELF) from central and peripheral airways separately collected using a bronchoscopic microsampling technique. 8-isoprostane levels in ELF from central or peripheral airways did not significantly differ between the two groups. However, these levels were markedly higher in peripheral than in central airways. Similarly, IL-8 levels in ELF from central airways did not significantly differ between the two groups. In smokers without airflow limitation, IL-8 levels were not higher in peripheral than in central airways. In contrast, in smokers with airflow limitation, IL-8 levels were significantly higher in peripheral airways. Moreover, in smokers with airflow limitation, 8-isoprostane levels in central or peripheral airways were not significantly correlated with FEV1. However, IL-8 levels in peripheral airways were inversely correlated with FEV1, though those levels in central airways were not. Thus our technique provides a novel method for ELF sampling from central or peripheral airways separately, and the preliminary evidence that support differences in oxidative stress and neutrophil chemotactic stimulus in these two locations. [Copyright &y& Elsevier]

Summary: 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, FEV1%predicted 89% (62–120), PC20 Methacholine (MCh) 0.4mg/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 N2 closing volume, FEF25–75%, FEF50% and % change in FVC at PC20 adenosine-5′-monophosphate (AMP) and at PC20MCh 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, 4nL/s (2–7) versus 2nL/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. [Copyright &y& Elsevier]

Inflammation is a key pathology in asthma. In the central airways local inflammation leads to irreversible remodeling and airway dysfunction. Complex inflammatory changes also occur in the nose, sinuses, and small airways. In particular, rhinitis and asthma are linked by a common pathogenic process with common inflammatory cells, mediators, and cytokines. Cross-communication between the airways and bone marrow through inflammatory mediators in the circulation leads to systemic propagation of airway inflammation. Treatment of asthma has traditionally focused on relieving bronchospasm with β2-agonists, which do not affect inflammation. Treatment of eosinophilic inflammation in the central airways with inhaled corticosteroids reduces local inflammation and improves pulmonary function but does not improve the systemic manifestations of asthma. If asthma is a systemic disease, the underlying systemic pathology should be targeted by identifying common disease mediators, mechanisms, or both that are triggered only during active disease. Of currently available therapies, leukotriene receptor antagonists block the action of cysteinyl leukotrienes and thus improve both asthma and rhinitis and other conditions systemically linked with asthma. Other potential treatments include receptor-blocking molecules and synthesis inhibitors related to eicosanoid inflammation. Treatment of asthma as a systemic disease requires clinical trials that evaluate the effects of new treatments on both lung function and the wider systemic pathology. [Copyright &y& Elsevier]

Background: Air trapping reflects small airway obstruction in asthma and can be assessed quantitatively by high-resolution computed tomography (HRCT). Hydrofluoroalkane-beclomethasone dipropionate (HFA-BDP) is deposited across all sizes of airways, including the small ones. However, its long-term effect on air trapping remains unknown in uncontrolled asthma. Objectives: To compare the effect of inhaled corticosteroids of different particle size—HFA-BDP and fluticasone propionate (FP)—on lung attenuation in mild-to-moderate uncontrolled asthma. Methods: A randomized study was performed to analyze the effect of HFA-BDP (400 μg/d) or FP (500 μg/d) given over a period of 3 months to patients with uncontrolled mild-to-moderate asthma. HRCT was performed with spirometric gating, and lung attenuation was measured at residual volume and at pulmonary total capacity. The difference between inspiratory and expiratory attenuation was calculated as an air trapping index. Results: Twenty-five out of 58 patients had abnormal air trapping and could be included in the study. Lung attenuation significantly diminished in the posterior zones of the lung after a 3-month treatment with HFA-BDP or FP, but the difference between the groups was not significant. Adjusted mean variations of the air trapping index from baseline to treatment completion were 34.3 (11.2, 57.3) and 27.3 (6.4, 48.2) for the HFA-BDP and FP groups, respectively. However, the reduction of air trapping area was more pronounced in the group treated with HFA-BDP. Conclusion: Inhaled corticosteroids decrease air trapping in uncontrolled asthma regardless of their particle size. Clinical implications: In mild-to-moderate asthma, air trapping assessed by HRCT may be a new outcome related to the control of the disease. [Copyright &y& Elsevier]

Background: Small airways may have an important role in asthma but are more difficult to assess pathologically than central airways. Computed tomographic indices of lung density are assumed to reflect air trapping and may be a useful noninvasive measure of small airways disease, but their pathophysiological relevance remains undetermined. Objective: To evaluate lung density on high-resolution computed tomography and examine its correlations with clinical and physiologic variables in 29 patients with stable asthma. Methods: Both lungs were scanned at full-inspiratory and full-expiratory phases to quantify percentage of lung field occupied by low attenuation area (LAA%; < −960 Hounsfield units) and mean lung density. Asthma severity, pulmonary function, methacholine airway sensitivity and reactivity, and sputum eosinophil counts were evaluated. Results: The mean lung density increased and LAA% decreased in all patients at expiratory phase compared with inspiratory phase. The inspiratory density indices and expiratory mean lung density correlated only with FEV1/forced vital capacity (FVC). Expiratory LAA% correlated more strongly than other variables with FEV1/FVC and with indices of peripheral airflow obstruction. Expiratory/inspiratory ratios of LAA% and mean lung density correlated, the former more strongly, with disease severity, residual volume/total lung capacity, and airway sensitivity, as well as with indices of global (FEV1 and FEV1/FVC) and peripheral airflow obstruction. Conclusion: Expiratory/inspiratory high-resolution computed tomography is useful for assessing small airways disease in asthma. Small airways involvement is associated with airflow obstruction, airway hypersensitivity, and more severe disease. Clinical implications: Small airways are an important therapeutic target in asthma. [Copyright &y& Elsevier]

Background: The target of anti-inflammatory therapy in asthma is thought to be situated, at least partly, in the lung periphery, and inhaled steroid aerosols are being engineered to reach it. However, the potential effect of such aerosols cannot be fully evaluated by conventional lung function tests because these are insensitive to peripheral lung structure. Objective: A prospective cohort study was conducted to investigate whether ultrafine steroid aerosols can elicit a response in the lung periphery, using a validated multibreath washout technique that can distinguish acinar from conductive lung zone function. Methods: In 30 stable patients with asthma with a wide range of disease severity (FEV1 27% to 108% predicted), we assessed conductive and acinar airway function abnormality at baseline, with patients on a standard dry powder steroid aerosol and after switching them to an ultrafine steroid aerosol. Results: Only in those patients with abnormal acinar airway function at baseline (n = 16) did acinar heterogeneity show a consistent improvement after switching to an ultrafine steroid aerosol; the improvement was also correlated with baseline acinar heterogeneity (r = −0.67; P = .007). Although all patients with asthma also presented conductive airway abnormality at baseline, no changes were observed in this lung zone with the switch to the ultrafine aerosol (P > .1). Conclusion: Among stable patients with asthma, those with acinar lung zone abnormality at baseline have the potential to receive functional benefit from an ultrafine steroid aerosol. Clinical studies comparing the efficacy of steroid aerosols targeted to the deep lung should at least include a measurement of peripheral lung zone function. Clinical implications: A new noninvasive measure of small airways function reveals why, and for which particular patients with asthma, small steroid aerosol particles can be of therapeutic use. [Copyright &y& Elsevier]

Summary: The N2 slope is an index of inhomogeneous distribution of ventilation and has been suggested to be suited for early testing of chronic obstructive pulmonary disease (COPD) in smokers. The aim of the present study was to examine the association between the fraction of exhaled nitric oxide (FENO) and the N2 slope in a random population of smoking and non-smoking men. Altogether 57 subjects were included in the study, 24 never-smokers, seven ex-smokers and 26 current smokers. Subjects were examined twice, in 1995 when they regarded themselves as healthy, and in a follow-up in 2001. Spirometry, N2 slope and high-resolution computed tomography (HRCT) were performed in 1995 while the follow-up examination included also measurement of FENO. The FENO value was significantly lower and the N2 slope higher in current smokers. In smokers but not in never- or ex-smokers FENO was correlated to the difference in N2 slope between 1995 and 2001 (, ). We analysed the data by multiple linear regression adjusted for smoking, mild respiratory symptoms and inhaled steroids. There were significant associations between FENO and the N2 slope both in 1995 and in 2001. The strongest association was found to exist with the change in N2 slope during these years. Sixteen of the subjects could be classified as having COPD, six with mild and ten with moderate COPD. There was a trend for an increase in N2 slope with increased severity of COPD; among subjects with no COPD the N2 slope in 2001 was 2.3% N2/L, and those with mild and moderate COPD had 2.5% N2/L and 3.9% N2/L, respectively (). No such trend was seen for FENO (17.8, 15.5 and 20.3 parts per billion (ppb), respectively, ). The results show that FENO is associated with the N2 slope, indicating that FENO reflects inflammatory changes in the peripheral airways of both non-smoking and smoking subjects. [Copyright &y& Elsevier]

Summary: The magnitude of improvement of respiratory symptoms (RS) and expiratory flows (EF) following corticosteroid treatment may vary from one asthmatic patient to another. The distribution of ratio of improvement of the above parameters was assessed in 937 patients with asthma of variable severity who took part in three clinical trials comparing the effects of chlorofluorocarbon-propelled beclomethasone dipropionate (CFC-BDP) with similar (n:316) or half-doses (n:581) of extrafine hydrofluoroalkane-propelled (HFA-BDP) on asthma control. We calculated the ratio of improvement of shortness of breath, wheezing, sleep disturbance, cough, and chest tightness over the following physiological parameters: forced expiratory volume in 1s (FEV1), FEF25/75%, morning peak expiratory flow, and FVC, from the baseline value to the last set of measures in the study, while on the study medication. We hypothesized that the ratio of RS/EF would have a normal distribution and would be higher with extrafine HFA-BDP compared with CFC-BDP, which has a larger particle size, when FEV1 is used, as it mostly assesses large airways. Ratios of improvement were normally distributed for both drugs and no significant shift in its distribution curve was found for HFA-BDP. The ratio of changes in FEF25/75%/FEV1 was similar in the two groups. In conclusion, the ratio of improvement of RS/EF is normally distributed over a narrow range, showing a generally good correlation between improvements in EF and symptoms in asthma; it was, however, similar for the two BDP molecules tested. This may suggest that this ratio is not useful for evaluating the effect of corticosteroids on small airways, or that extrafine HFA-BDP acts at the level of large- to moderate-caliber airways to produce most of its beneficial effect. [Copyright &y& Elsevier]

Abstract: Chronic obstructive pulmonary disease (COPD) exacerbations are an important cause of the considerable morbidity and mortality found in COPD. COPD exacerbations increase with increasing severity of COPD, and some patients are prone to frequent exacerbations leading to hospital admission and readmission. These frequent exacerbations may have considerable impact on quality of life and activities of daily living. Factors that increase the risk for COPD exacerbations are associated with increased airway inflammation caused by common pollutants and bacterial and/or viral infections. These inflammatory responses cause mucus hypersecretion and, thereby, airway obstruction and associated exacerbations. While chronic mucus hypersecretion is a significant risk factor for frequent and severe exacerbations, patients with chronic mucus hypersecretion have a lower rate of relapse after initial treatment for acute exacerbation. The benefit of antibiotics for treatment of COPD exacerbations is small but significant. While the mechanisms of actions are not clear, mucolytic agents reduce the number of days of disability in subjects with exacerbations. Reducing mucous cell numbers in small airways could be a useful way to reduce chronic mucus hypersecretion. Our studies suggest that programmed cell death is crucial in the resolution of metaplastic mucous cells, and understanding these mechanisms may provide novel therapies to reduce the risk of COPD exacerbations. [Copyright &y& Elsevier]

Abstract: Lung transplantation is now accepted as a viable therapeutic option for patients with end-stage lung diseases, but long-term survival is threatened by bronchiolitis obliterans (BO), which is regarded as a manifestation of chronic allograft rejection. We have used studies of ventilation distribution for the early detection of this complication. In a prospective study of 57 bilateral-lung transplant recipients, we showed that the slope of phase III of the helium single-breath washout, which targets inhomogeneities of ventilation distribution in the terminal and respiratory bronchioles, was particularly sensitive to the development of BO. In a preliminary study using nitrogen multiple-breath washouts, we showed that S acin and S cond, which reflect structural changes in the acinar and conductive lung zones, were both markedly increased in patients with BO. Taken together, these studies demonstrate that monitoring the function of the allograft by measuring the distribution of ventilation in the lung periphery may be a clinically valuable tool. [Copyright &y& Elsevier]

A transversal survey was performed in order to assess asthma control in usual practice, and to evaluate, the existence and extent of small airway impairment in non-controlled asthma. This survey was performed between September and November 2000 by 420 urban pneumologists on 1,333 adult asthmatic patients referring for scheduled pulmonary function tests. Asthma control was assessed following two approaches: qualitatively by the physician’s interview about functional signs, and quantitatively by the patient with the help of the Juniper questionnaire for asthma control. Small airway impairment was defined as a decrease in the distal flows greater than 50% or distension (residual volume or forced vital capacity > 120% of predicted values). Compared to clinical evaluation, a value < 1.25 for the Juniper score is predictive of good asthma control: P < 0.0001, sensibility 84%, specificity 91%, confidence interval between 0.65 and 0.73. Distal airway impairment was more frequent in case of poorly controlled asthma (score ≥ 1.25). This survey shows the interest of the quantitative evaluation of asthma control by the patients by means of the questionnaire of Juniper, a mean score of 1.25 having the best comparative value with the clinical assessment by the physician. It also shows a good correlation between an elevated score of Juniper and the degree of small airway impairment, suggesting to optimise the anti-inflammatory treatment while directing it on the whole bronchial tract, including small airways. [Copyright &y& Elsevier]

Background Whether small-airway obstruction contributes to the long-term evolution of asthma remains unknown. Objectives Our aim was to assess whether the level of forced midexpiratory flow between 25% and 75% of forced vital capacity (FEF 25-75 ) was associated with the persistence of current asthma over 20 years and the subsequent risk for uncontrolled asthma independently of FEV 1 . Methods We studied 337 participants (142 children and 225 adults) with current asthma (asthma attacks or treatment in the past 12 months) recruited to the Epidemiological Study on the Genetics and Environment of Asthma (EGEA1) and followed up at the 12- and 20-year surveys. Persistent current asthma was defined by current asthma reported at each survey. A lung function test and a methacholine challenge test were performed at EGEA1 and EGEA2. Adjusted odds ratios (ORs) were estimated for FEF 25-75 decreased by 10% of predicted value. Results A reduced level of FEF 25-75 at EGEA1 increased the risk of long-term asthma persistence (adjusted OR, 1.14; 95% CI, 1.00-1.29). In children the association remained significant after further adjustment for FEV 1 and in participants with FEV 1 of greater than 80% of predicted value. A reduced FEF 25-75 level at EGEA1 was significantly associated with more severe bronchial hyperresponsiveness ( P < .0001) and with current asthma a decade later, with an association that tended to be stronger in those with (adjusted OR, 1.44; 95% CI, 1.14-1.81) compared with those without (adjusted OR, 1.21; 95% CI, 1.05-1.41) asthma exacerbation. Conclusion Our analysis is the first to suggest that small-airway obstruction, as assessed based on FEF 25-75 , might contribute to the long-term persistence of asthma and the subsequent risk for poor asthma outcomes independently from effects of the large airways. [ABSTRACT FROM AUTHOR]

Background Effects of small-particle long-acting β-agonists on the small airways have been poorly documented. Objective We used impulse oscillometry (IOS) to compare single and repeated dosing effects of small- and large-particle long-acting β-agonists. Methods After a 1- to 2-week run-in period, patients received either 12 μg of small-particle hydrofluoroalkane 134a–formoterol solution or 50 μg of large-particle salmeterol dry powder twice daily plus inhaled corticosteroid for 1 to 2 weeks with a 1- to 2-week washout period in between. Measurements were made over 60 minutes after the first and last doses. Results Sixteen patients completed the study as follows: mean age, 43 years; FEV 1 , 80%; forced midexpiratory flow between 25% and 75% of forced vital capacity (FEF 25-75 ), 48%; total airway resistance at 5 Hz, 177%; peripheral airway resistance as the difference between 5 and 20 Hz, 0.18 kPa·L −1 ·s; Asthma Control Questionnaire score, 0.76; and inhaled corticosteroid dosage, 550 μg/d. There were significantly greater improvements with formoterol versus salmeterol in all IOS outcomes and FEF 25-75 , but not FEV 1 , at 5 minutes after the first dose, which were not sustained over 60 minutes. After the last dose, all IOS outcomes, but not FEV 1 or FEF 25-75 , were significantly better with formoterol over the entire 60 minutes: mean difference at 60 minutes between formoterol and salmeterol in total airway resistance at 5 Hz, 7.50% (95% CI, 1.56% to 13.43%, P = .02); central airway resistance at 20 Hz, 5.37% (95% CI, 0.13% to 10.62%, P = .045); peripheral airway resistance as the difference between 5 and 20 Hz, 12.76% (95% CI, 1.28% to 24.24%, P = .03); reactance area under the curve, 19.46% (95% CI, 7.56% to 31.36%, P = .003); reactance at 5 Hz, 11.19% (95% CI, 4.62% to 17.76%, P = .002); and resonant frequency, 9.34% (95% CI, 3.21% to 15.47%, P = .005). Peak expiratory flow significantly improved to a similar degree with both drugs. Conclusion Significant improvements in IOS outcomes but not spirometry results occurred after chronic dosing with formoterol compared with salmeterol. This might reflect better deposition to the entire lung, including the small airways. [ABSTRACT FROM AUTHOR]

Background: The clinical relevance of increased ventilation heterogeneity, a marker of small-airways disease, in asthmatic patients is unclear. Ventilation heterogeneity is an independent determinant of airway hyperresponsiveness (AHR), improves with bronchodilators and inhaled corticosteroids (ICSs), and worsens during exacerbations, but its relationship to asthma control is unknown. Objective: We sought to determine the association between ventilation heterogeneity and current asthma control before and after ICS treatment. Methods: Adult subjects with asthma had lung function and asthma control (5-item Asthma Control Questionnaire [ACQ-5 score] ≥1.5 = poorly controlled, ACQ-5 score ≤0.75 = well controlled) measured at baseline. A subgroup with AHR had repeat measurements after 3 months of high-dose ICS treatment. The indices of ventilation heterogeneity in the regions of the lung where gas transport occurs predominantly through convection (ventilation heterogeneity in convection-dependent airways [Scond]) and through diffusion (ventilation heterogeneity in diffusion-dependent airways [Sacin]) were derived by using the multiple-breath nitrogen washout technique. Results: At baseline (n = 105), subjects with poorly controlled asthma had worse FEV1, fraction of exhaled nitric oxide measured at 200 mL/s (Feno), Scond, and Sacin values. In the treatment group (n = 50) spirometric, Feno, residual volume (RV)/total lung capacity (TLC), AHR, and Scond values significantly improved. Asthma control also improved (mean ACQ-5 score, 1.3-0.7; P < .0001). The change in ACQ-5 score correlated with changes in Feno (rs  = 0.31, P = .03), Sacin (rs  = 0.32, P = .02), and Scond (rs  = 0.41, P = .003) values. The independent predictors of a change in asthma control were changes in Scond and Sacin values (model r2  = 0.20, P = .005). Conclusions: Current asthma control is associated with markers of small-airways disease. Improvements in ventilation heterogeneity with anti-inflammatory therapy are associated with improvements in symptoms. Sensitive measures of small-airway function might be useful in monitoring the response to therapy in asthmatic subjects. [ABSTRACT FROM AUTHOR]

Asthma remains a major problem worldwide, even with new categories of medications that have been brought into the therapeutic armamentarium. One area of disease pathology and physiology that is involved in the pathobiology of asthma is the distal (small) airways. Better understanding of this area in both the pediatric and adult asthmatic populations will lead to improved targeted therapy for all asthmatic patients. This article discusses the importance of the distal airways for both children and adults with asthma. [Copyright &y& Elsevier]

Imaging techniques of the lung continue to advance, with improving ability to image the more distal airways. Two imaging techniques are reviewed: computed tomography and magnetic resonance with hyperpolarized helium-3. [Copyright &y& Elsevier]

This article covers the airway tree with respect to anatomy, pathology, and physiology. The anatomic portion discusses various primate groups so as to help investigators understand similarities and differences between animal models. An emphasis is on distal airway findings. The pathology section focuses on the inflammatory responses that occur in proximal and distal airways. The physiologic review brings together the anatomic and pathologic components to the functional state and proposes ways to evaluate the small airways in patients with asthma. [Copyright &y& Elsevier]