Pulmonary physiology: future directions for lung function testing in COPD.

Chronic obstructive pulmonary disease (COPD) is a term that encompasses different pathological conditions having excessive airflow limitation in common. A wide body of knowledge has been accumulated over the last century explaining the mechanisms by which airway (chronic bronchitis) and parenchymal (emphysema) diseases lead to an indistinguishable spirometric abnormality. Although the definition of emphysema is anatomical, early studies showed that its presence can be inferred with good approximation from measurements of lung mechanics and gas exchange, in addition to simple spirometry. Studies using tests of ventilation distribution showed that abnormalities are present in smokers with normal spirometry, although these tests were not predictive of development of COPD. At the beginning of the third millennium, new documents and guidelines for diagnosis and treatment of COPD were developed, in which the functional diagnosis of COPD was restricted, for the sake of simplicity, to simple spirometry. In recent years, there has been a resurgence of interest in separating bronchitic from emphysematous phenotype of COPD. For this purpose, high-resolution computed tomography scanning has been added to diagnostic work-up. At the same time, methods for lung function testing have been refined and seem promising for detection of early small airways abnormalities. Among them are the forced oscillation technique and the nitrogen phase III slope analysis of the multiple-breath washout test, which may provide information on ventilation inhomogeneity. Moreover, the combined assessment of diffusing capacity for nitric oxide and carbon monoxide may be more sensitive than the latter alone for partitioning diffusive components at parenchymal level.

Dependence of bronchoconstrictor and bronchodilator responses on thoracic gas compression volume.

BACKGROUND AND OBJECTIVE: During forced expiration, alveolar pressure (PALV ) increases and intrathoracic gas is compressed. Thus, 1-s forced expiratory volume measured by spirometry (FEV1-sp ) is smaller than 1-s forced expiratory volume measured by plethysmography (FEV1-pl ). Thoracic gas compression volume (TGCV) depends on the amount of gas within the lung when expiratory flow limitation occurs in the airways. We therefore tested the hypothesis that bronchoconstrictor and bronchodilator responses using FEV1-sp are biased by height and gender, which are major determinants of lung volume. METHODS: We studied 54 asthmatics during methacholine challenge and 55 subjects with airway obstruction (FEV1-sp increase >200 mL and >12% after salbutamol) measuring at the same time FEV1-sp or FEV1-pl . RESULTS: During methacholine challenge, TGCV increased more in males than females, correlated with PALV , total lung capacity (TLC) and height, and the provocative dose was lower using FEV1-sp than FEV1-pl . With salbutamol, FEV1-pl increased <200 mL and <12% in 28 subjects, predominantly tall males, with larger TLC, TGCV and PALV . CONCLUSIONS: Bronchoconstrictor and bronchodilator responses are overestimated by standard spirometry in subjects with larger lungs because of TGCV.

Bronchodilator effects of exercise hyperpnea and albuterol in mild-to-moderate asthma.

In asthmatic patients, either bronchodilatation or bronchoconstriction may develop during exercise. In 18 patients with mild-to-moderate asthma, we conducted two studies with the aims to 1) quantify the bronchodilator effect of hyperpnea induced by incremental-load maximum exercise compared with effects of inhaled albuterol (study 1, n=10) and 2) determine the time course of changes in airway caliber during prolonged constant-load exercise (study 2, n=8). In both studies, it was also investigated whether the bronchodilator effects of exercise hyperpnea and albuterol are additive. Changes in airway caliber were measured by changes in partial forced expiratory flow. In study 1, incremental-load exercise was associated with a bronchodilatation that was approximately 60% of the maximal bronchodilatation obtainable with 1,500 microg of albuterol. In study 2, constant-load exercise was associated with an initial moderate bronchodilatation and a late airway renarrowing. In both studies, premedication with inhaled albuterol (400 microg) promoted sustained bronchodilatation during exercise, which was additive to that caused by exercise hyperpnea. In conclusion, in mild-to-moderate asthmatic individuals, hyperpnea at peak exercise was associated with a potent yet not complete bronchodilatation. During constant-load exercise, a transient bronchodilatation was followed by airway renarrowing, suggesting prevalence of constrictor over dilator effects of hyperpnea. Finally, the bronchodilator effect of hyperpnea was additive to that of albuterol.

Airway responsiveness to methacholine and deep inhalations in subjects with rhinitis without asthma.

BACKGROUND: Airway hyperresponsiveness in asthma is believed to be caused in part by the inability of deep inspirations to modulate airway narrowing. OBJECTIVE: We investigated whether deep inspirations taken before or after methacholine inhalation attenuate bronchoconstriction in subjects with rhinitis. The results were compared with a group of healthy subjects. METHODS: Ten subjects with rhinitis without asthma and 10 healthy subjects were studied on 3 different occasions at random. Bronchial challenges were performed with a single dose of methacholine known to decrease the FEV(1) by 17% to 40%. Challenges were performed with avoidance of deep inspirations, or with 5 deep inspirations preceding or following the inhalation of methacholine. Lung function measurements were specific airway conductance, forced expiratory flow at 30% to 40% of vital capacity on a maneuver started from end-tidal inspiration (partial flow), and residual volume (partial residual volume). RESULTS: In healthy subjects, deep inspirations taken after methacholine caused less changes in specific airway conductance, partial flow, and partial residual volume (P < .005 for all) than deep inspirations taken before methacholine or avoidance. In subjects with rhinitis, methacholine produced similar functional changes independently of the presence or absence of any deep inspirations. Compared with normal subjects, the attenuating effects of deep inspirations after methacholine on partial flow and partial residual volume were blunted in the subjects with rhinitis (P = .02 and P = .05, respectively). CONCLUSION: The ability to dilate methacholine-constricted airways by deep inspirations is impaired in subjects with rhinitis, possibly because of an abnormal behavior of airway smooth muscle.

Allergic airway inflammation and beta-adrenoceptor dysfunction.

A reduced response to beta-adrenoceptor agonists has been reported in airways of asthmatic subjects. Mechanisms for beta-adrenoceptor dysfunction are (1) inactivation or downregulation of beta-adrenoceptors by specific agonists (homologous desensitization) or by inflammatory mediations (heterologous desensitization), (2) inactivation or downregulation of second messengers of beta-adrenoceptor pathway. Studies from our laboratory have shown that allergen challenge of passively sensitized human bronchi causes a beta-adrenoceptor dysfunction as a result of reduced activity of the receptor-coupled Gs protein. The dysfunction was prevented by leukotriene-receptor antagonists or a cell membrane stabilizer, but not by an antihistimine or indomethacin, suggesting a central role of leukotrienes released from resident inflammatory cells in its genesis. Furthermore, the beta-adrenoceptor response and Gs protein function after allergen exposure were restored by short-term (3 h) incubation with beclomethasone dipropionate, suggesting an effect independent of gene transcription. Restoration of the intracellular beta-adrenoceptor effector pathway may contribute to the efficacy of corticosteroids in the acute treatment of asthma.

Cysteinyl-leukotrienes in the regulation of beta2-adrenoceptor function: an in vitro model of asthma.

BACKGROUND: The response to beta2-adrenoceptor agonists is reduced in asthmatic airways. This desensitization may be in part due to inflammatory mediators and may involve cysteinyl-leukotrienes (cysteinyl-LTs). Cysteinyl-LTs are pivotal inflammatory mediators that play important roles in the pathophysiology of asthma, allergic rhinitis, and other inflammatory conditions. We tested the hypothesis that leukotriene D4 (LTD4) and allergen challenge cause beta2-adrenoceptor desensitization through the activation of protein kinase C (PKC). METHODS: The isoproterenol-induced cAMP accumulation was evaluated in human airway smooth muscle cell cultures challenged with exogenous LTD4 or the PKC activator phorbol-12-myristate-13-acetate with or without pretreatments with the PKC inhibitor GF109203X or the CysLT1R antagonist montelukast. The relaxant response to salbutamol was studied in passively sensitized human bronchial rings challenged with allergen in physiological salt solution (PSS) alone, or in the presence of either montelukast or GF109203X. RESULTS: In cell cultures, both LTD4 and phorbol-12-myristate-13-acetate caused significant reductions of maximal isoproterenol-induced cAMP accumulation, which were fully prevented by montelukast and GF109203X, respectively. More importantly, GF109203X also prevented the attenuating effect of LTD4 on isoproterenol-induced cAMP accumulation. In bronchial rings, both montelukast and GF109203X prevented the rightward displacement of the concentration-response curves to salbutamol induced by allergen challenge. CONCLUSION: LTD4 induces beta2-adrenoceptor desensitization in human airway smooth muscle cells, which is mediated through the activation of PKC. Allergen exposure of sensitized human bronchi may also cause a beta2-adrenoceptor desensitization through the involvement of the CysLT1R-PKC pathway.

Attenuation of induced bronchoconstriction in healthy subjects: effects of breathing depth.

The effects of breathing depth in attenuating induced bronchoconstriction were studied in 12 healthy subjects. On four separate, randomized occasions, the depth of a series of five breaths taken soon (approximately 1 min) after methacholine (MCh) inhalation was varied from spontaneous tidal volume to lung volumes terminating at approximately 80, approximately 90, and 100% of total lung capacity (TLC). Partial forced expiratory flow at 40% of control forced vital capacity (V(part)) and residual volume (RV) were measured at control and again at 2, 7, and 11 min after MCh. The decrease in V(part) and the increase in RV were significantly less when the depth of the five-breath series was progressively increased (P < 0.001), with a linear relationship. The attenuating effects of deep breaths of any amplitude were significantly greater on RV than V(part) (P < 0.01) and lasted as long as 11 min, despite a slight decrease with time when the end-inspiratory lung volume was 100% of TLC. In conclusion, in healthy subjects exposed to MCh, a series of breaths of different depth up to TLC caused a progressive and sustained attenuation of bronchoconstriction. The effects of the depth of the five-breath series were more evident on the RV than on V(part), likely due to the different mechanisms that regulate airway closure and expiratory flow limitation.

Severity grading of chronic obstructive pulmonary disease: the confounding effect of phenotype and thoracic gas compression.

Current guidelines recommend severity of chronic obstructive pulmonary disease be graded by using forced expiratory volume in 1 s (FEV1). But this measurement is biased by thoracic gas compression depending on lung volume and airflow resistance. The aim of this study was to test the hypothesis that the effect of thoracic gas compression on FEV1 is greater in emphysema than chronic bronchitis because of larger lung volumes, and this influences severity classification and prognosis. FEV1 was simultaneously measured by spirometry and body plethysmography (FEV1-pl) in 47 subjects with dominant emphysema and 51 with dominant chronic bronchitis. Subjects with dominant emphysema had larger lung volumes, lower diffusion capacity, and lower FEV1 than those with dominant chronic bronchitis. However, FEV1-pl, patient-centered variables (dyspnea, quality of life, exercise tolerance, exacerbation frequency), arterial blood gases, and respiratory impedance were not significantly different between groups. Using FEV1-pl instead of FEV1 shifted severity distribution toward less severe classes in dominant emphysema more than chronic bronchitis. The body mass, obstruction, dyspnea, and exercise (BODE) index was significantly higher in dominant emphysema than chronic bronchitis, but this difference significantly decreased when FEV1-pl was substituted for FEV1. In conclusion, the FEV1 is biased by thoracic gas compression more in subjects with dominant emphysema than in those with chronic bronchitis. This variably and significantly affects the severity grading systems currently recommended.

Deep breaths, methacholine, and airway narrowing in healthy and mild asthmatic subjects.

Deep breaths taken before inhalation of methacholine attenuate the decrease in forced expiratory volume in 1 s and forced vital capacity in healthy but not in asthmatic subjects. We investigated whether this difference also exists by using measurements not preceded by full inflation, i.e., airway conductance, functional residual capacity, as well as flow and residual volume from partial forced expiration. We found that five deep breaths preceding a single dose of methacholine 1) transiently attenuated the decrements in forced expiratory volume in 1 s and forced vital capacity in healthy (n = 8) but not in mild asthmatic (n = 10) subjects and 2) increased the areas under the curve of changes in parameters not preceded by a full inflation over 40 min, during which further deep breaths were prohibited, without significant difference between healthy (n = 6) and mild asthmatic (n = 16) subjects. In conclusion, a series of deep breaths preceding methacholine inhalation significantly enhances bronchoconstrictor response similarly in mild asthmatic and healthy subjects but facilitates bronchodilatation on further full inflation in the latter.

Exercise-induced bronchodilation in natural and induced asthma: effects on ventilatory response and performance.

We studied whether bronchodilatation occurs with exercise during the late asthmatic reaction (LAR) to allergen (group 1, n = 13) or natural asthma (NA; group 2, n = 8) and whether this is sufficient to preserve maximum ventilation (VE(max)), oxygen consumption (VO(2 max)), and exercise performance (W(max)). In group 1, partial forced expiratory flow at 30% of resting forced vital capacity increased during exercise, both at control and LAR. W(max) was slightly reduced at LAR, whereas VE(max), tidal volume, breathing frequency, and VO(2 max) were preserved. Functional residual capacity and end-inspiratory lung volume were significantly larger at LAR than at control. In group 2, partial forced expiratory flow at 30% of resting forced vital capacity increased greatly with exercise during NA but did not attain control values after appropriate therapy. Compared with control, W(max) was slightly less during NA, whereas VO(2 max) and VE(max) were similar. Functional residual capacity, but not end-inspiratory lung volume at maximum load, was significantly greater than at control, whereas tidal volume decreased and breathing frequency increased. In conclusion, remarkable exercise bronchodilation occurs during either LAR or NA and allows VE(max) and VO(2 max) to be preserved with small changes in breathing pattern and a slight reduction in W(max).

Modulation of cholinergic responsiveness through the [beta]-adrenoceptor signal transmission pathway in bovine trachealis.

The effects of pharmacological stimulation at different levels of the beta-adrenoceptor (AR) pathway, including the receptor, the receptor-coupled Gs protein, and adenylyl cyclase, were studied by simultaneous measurements of acetylcholine (ACh) release and isometric force evoked by electric stimulation in isolated bovine trachealis. The beta-AR agonists isoproterenol (10-6 and 10-5 M) and salbutamol (10-7 to 10-5 M) significantly attenuated both ACh release and contractile force. Forskolin, at 10-6 M, significantly increased ACh release without effect on contractile force, whereas at 10-5 M it increased ACh release but significantly decreased force. Activation of Gs protein by cholera toxin (10 microg/ml) significantly attenuated both ACh release and contractile force, but its effect on ACh release was abolished by calcium-activated potassium (KCa)-channel blocker iberiotoxin (10-7 M). The KCa-channel opener NS-1619 (10-4 M) attenuated significantly both ACh release and contractile force. It is concluded that beta-AR agonists attenuate cholinergic neurotransmission in isolated bovine trachealis model by a mechanism not involving cAMP but KCa channels.

Airway reactivity and diving in healthy and atopic subjects.

BACKGROUND: The short- and long-term effects of self-contained underwater breathing apparatus (SCUBA) dives on airway responsiveness in nonasthmatic atopic subjects have not been systematically investigated. PURPOSE: To compare the effect of SCUBA diving at 50-m depth on lung function and airway responsiveness to methacholine (MCh) in atopic nonasthmatics and healthy subjects. METHODS: We studied 15 atopic nonasthmatic subjects and 15 controls who underwent the visit for the professional SCUBA-diving license at the Navy Medical Center, La Spezia, Italy. All subjects underwent spirometry and skin-prick test for common environmental allergens. MCh challenge was performed 24 h before, and 20 min and 24 h after a standardized SCUBA-dive test and after hyperbaric-chamber test. RESULTS: At 20 min, the provocative dose of MCh causing 20% fall of the forced expiratory volume at the first second (MCh PD20 - FEV1) was significantly reduced in atopic, asymptomatic subjects from 1712 x 2.6 microg (mean x geometric standard deviation) to 1202 x 2.2 microg (P < 0.0005) after the hyperbaric-chamber test and to 1204 x 2.3 microg (P < 0.005) after SCUBA diving. In healthy subjects, the baseline value of MCh PD20 was 2977 x 1.1 microg, and this value did not change significantly after the hyperbaric-chamber test (2575 x 1.4 microg) and after SCUBA dives (2553 x 1.4 microg, P > 0.1 for both comparisons). In atopic subjects, the MCh PD20 returned near to the baseline value 24 h after the hyperbaric-chamber test (1776 x 2.4 microg) and after the SCUBA test (1500 x 2.67 microg). No significant change in FEV1 was observed after the tests in both groups. CONCLUSION: SCUBA diving is associated with development of early airway hyperresponsiveness to MCh in atopic subjects.

Lung function testing in COPD: when everything is not so simple.

Combined pulmonary fibrosis and emphysema is a condition occurring mainly in male smokers, presenting different lung mechanics and gas exchange abnormalities than emphysema or pulmonary fibrosis alone. We report the case of an elderly man, former heavy smoker, who presented with progressive exertional dyspnea for 1 year. Lung function tests showed near normal spirometry and lung volumes but marked reduction of diffusing capacity for carbon monoxide and even more nitric oxide. The arterial partial pressure of oxygen was reduced with a markedly increased alveolar-to-arterial difference. High-resolution computed tomography of the chest showed a pattern consistent with upper lobe emphysema and lower lobe pulmonary fibrosis. In conclusion, this case report confirms the limitations of a simplistic approach to lung function in the diagnosis of symptomatic smokers.

Effects of κ- and µ-opioid agonists on cholinergic neurotransmission and contraction in isolated bovine trachealis.

The effects of the selective µ-opioid agonist DAMGO and the selective κ-opioid agonist U-50488H on tritiated acetylcholine release ([(3)H]-ACh) and contractile responses to electrical stimulation (ES) were simultaneously determined in isolated bovine trachealis. The inhibitory effect of DAMGO 10(-5)M on [(3)H]-ACh release was not significantly different from the effect of the non-selective muscarinic agonist pilocarpine 10(-5)M, whereas the effect of U-50488H 10(-5)M was significantly greater. The effects of both opioids were not significantly different when muscles were pre- or co-incubated with the unselective muscarinic antagonist atropine 10(-7)M. Both DAMGO and U-50488H attenuated ES-induced contraction and this effect was significantly correlated with the inhibition of [(3)H]ACh-release (r(2)=0.8552). These data suggest that (1) opioids are important modulators of airway smooth muscle tone, (2) their effect is not altered by the activity of muscarinic autoregulation, and (3) their inhibitory effect of airway smooth muscle contraction can be almost totally explained by inhibition of ACh release.

Gz- and not Gi-proteins are coupled to pre-junctional µ-opioid receptors in bovine airways.

We investigated the signal transmission pathway by which activation of µ-opioid receptors attenuates acetylcholine (ACh) release in bovine trachealis. Electrical stimulation (ES)-induced [(3)H]-ACh release was determined in bovine tracheal smooth muscle strips pre-incubated with either the Gi-protein inhibitor pertussis toxin (PTX, 500 ng/ml and 1 µg/ml) or the Gz-protein specific inhibitor arachidonic acid (AA, 10(-6)M and 10(-5)M) and then treated with DAMGO (D-Ala(2),N-MePhe(4),Gly-ol(5)-enkephalin) 10(-5)M. Indomethacin 10(-5)M was used to block AA cascade. The inhibitory effect of DAMGO on ES-induced [(3)H]-ACh release was PTX-insensitive, but, by contrast, ablated by AA in a concentration-dependent manner. AA 10(-5)M alone reduced [(3)H]-ACh release, an effect that was prevented by iberiotoxin 10(-7)M, suggesting an involvement of Ca(2+)-activated K(+)-channels. Western blot analysis consistently showed immunoreactive bands against a specific antibody anti-Gz-α subunit at ∼40 kDa, consistent with the presence of Gz-protein. The present findings suggest that in isolated bovine trachealis, activation of µ-opioid receptors inhibits ACh-release through a signal transmission pathway involving Gz-protein rather than Gi-protein.

Mechanical correlates of dyspnea in bronchial asthma.

We hypothesized that dyspnea and its descriptors, that is, chest tightness, inspiratory effort, unrewarded inspiration, and expiratory difficulty in asthma reflect different mechanisms of airflow obstruction and their perception varies with the severity of bronchoconstriction. Eighty-three asthmatics were studied before and after inhalation of methacholine doses decreasing the 1-sec forced expiratory volume by ~15% (mild bronchoconstriction) and ~25% (moderate bronchoconstriction). Symptoms were examined as a function of changes in lung mechanics. Dyspnea increased with the severity of obstruction, mostly because of inspiratory effort and chest tightness. At mild bronchoconstriction, multivariate analysis showed that dyspnea was related to the increase in inspiratory resistance at 5 Hz (R 5) (r (2) = 0.10, P = 0.004), chest tightness to the decrease in maximal flow at 40% of control forced vital capacity, and the increase in R 5 at full lung inflation (r (2) = 0.15, P = 0.006), inspiratory effort to the temporal variability in R 5-19 (r (2) = 0.13, P = 0.003), and unrewarded inspiration to the recovery of R 5 after deep breath (r (2) = 0.07, P = 0.01). At moderate bronchoconstriction, multivariate analysis showed that dyspnea and inspiratory effort were related to the increase in temporal variability in inspiratory reactance at 5 Hz (X 5) (r (2) = 0.12, P = 0.04 and r (2) = 0.18, P < 0.001, respectively), and unrewarded inspiration to the decrease in X 5 at maximum lung inflation (r (2) = 0.07, P = 0.04). We conclude that symptom perception is partly explained by indexes of airway narrowing and loss of bronchodilatation with deep breath at low levels of bronchoconstriction, but by markers of ventilation heterogeneity and lung volume recruitment when bronchoconstriction becomes more severe.

Pulmonary function and airway responsiveness in young competitive swimmers.

RATIONALE: Strong physical activities are often associated with large lung volumes and relatively reduced flow, which may represent a physiological variant but also an obstructive abnormality. Competitive swimmers have also spirometric values even larger than other athletes, although they are at increased risk for asthma or airway hyperresponsiveness. AIM: We aimed to investigate whether lung volumes increase with duration of swimming training and are related to an obstructive abnormality associated with airway hyperresponsiveness and asthma-like symptoms. METHODS: Forced expiratory volume in 1 sec (FEV(1)), forced vital capacity (FVC), airway responsiveness, and skin prick test were measured in 34 children/adolescents (age: 7-19 yrs old) trained for competitive swimming. Their "lifetime" exposure, i.e., the hours spent in pool was very strongly correlated with their age at the time of study. The effect of swimming activity was therefore estimated from the relationships between lung function data and age. RESULTS: FVC Z-score was positively correlated with age, indicating that absolute values increased more than expected with normal growth, but FEV(1)/FVC was negatively correlated with age. Although the majority of subjects had allergic sensitization to aeroallergens and about one half had asthma-like symptoms and/or airway hyperresponsiveness, these conditions did not alter the relationships between lung function and age. CONCLUSION: Intense swimming activity may cause a greater than normal lung growth, irrespective of the presence of allergic sensitization or airway hyperresponsiveness. The associated reduction of FEV(1) /FVC may represent a physiological variant rather than a true obstructive abnormality.

Pre-junctional muscarinic autoreceptors in bovine airways.

UNLABELLED: We searched for pre-junctional inhibitory muscarinic receptors in isolated bovine trachealis strips and bronchial rings. Electric stimulation (ES)-induced tritiated acetylcholine ([(3)H]-ACh)-release and isometric contractions were determined in muscles incubated with the non-selective muscarinic agonist pilocarpine, the non-selective muscarinic antagonist atropine, the selective M(2)-receptor antagonists methoctramine and gallamine, or the selective M(4)-receptor antagonist PD102807. Electric field stimulation (EFS)-induced isometric contractile responses were assessed in trachealis strips and bronchial rings treated with 10(-9)-10(-5)M methoctramine, gallamine or PD102807. Pilocarpine (10(-6) and 10(-5)M) and atropine (10(-7)M) significantly decreased and increased ES-evoked [(3)H]-ACh-release, respectively. The enhancing effect of atropine on [(3)H]-ACh-release prevailed over the inhibitory effect of pilocarpine. M(2)- and M(4)-receptor antagonists did not increase EFS-induced contraction or ES-induced [(3)H]-ACh-release. However, 10(-7)M methoctramine, gallamine or PD102807 significantly attenuated the inhibitory effects of pilocarpine 10(-5)M on ES-induced [(3)H]-ACh-release. CONCLUSIONS: Muscarinic autoregulation is present in bovine airways but is not fully accounted for by M(2)- and M(4)-receptor subtypes.

Acute bronchodilator responsiveness in bronchiolitis obliterans syndrome following hematopoietic stem cell transplantation.

BACKGROUND: The obstructive abnormality of bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic stem cell transplantation (HSCT) is deemed to be virtually insensitive to treatment with inhaled bronchodilators. We studied whether nonconventional assessment of bronchodilation may help to detect physiologically meaningful airway responses missed by traditional criteria. METHODS: Standard spirometry, partial and maximal expiratory flow-volume curves, and lung volumes were measured before and 90 min after inhalation of albuterol plus tiotropium in 17 patients who developed mild to very severe BOS following HSCT. RESULTS: After treatment with bronchodilators, the standard criteria of reversibility based on FEV1 and FVC were met in seven out of 17 patients. In eight patients, residual volume (RV) decreased beyond its within-session spontaneous variability, and functional residual capacity (FRC) was reduced in four of them. Partial forced expiratory flow (Vpart) increased beyond its within-session spontaneous variability in nine patients. Out of 10 patients in whom neither FEV1 nor FVC met the standard criteria of reversibility, six had a positive increase in Vpart or a decrease of lung hyperinflation (ie, FRC) or RV. In six patients with limited expiratory flow during tidal breathing, the postbronchodilator increase in Vpart was correlated with a decrease in FRC (R2=0.83; P=.011). CONCLUSIONS: This study suggests that airway smooth muscle tone plays a significant role in BOS after HSCT and that the common knowledge of BOS as an irreversible obstructive disease may stem from the limitation of simple spirometry to detect changes in small airways. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01112241 (BOS-01); URL: www.clinicaltrials.gov.

Formoterol by pressurized metered-dose aerosol or dry powder on airway obstruction and lung hyperinflation in partially reversible COPD.

BACKGROUND: We compared the efficacy and safety of formoterol given by a pressurized metered-dose inhaler (pMDI) (Atimos®, Chiesi Farmaceutici, Italy), using a chlorine-free hydrofluoroalkane (HFA-134a) propellant developed to provide stable and uniform dose delivery (Modulite™, Chiesi Farmaceutici, Italy), with formoterol by dry powder inhaler (DPI) (Foradil® Aerolizer®, Novartis Pharmaceuticals) and placebo, in reducing airflow obstruction and lung hyperinflation, in moderate-to-severe, partially reversible chronic obstructive pulmonary disease (COPD). METHODS: Forty-eight patients were randomized to a 1-week, double-blind, double-dummy, three-period crossover study with 12 µg b.i.d. of formoterol given by pMDI or DPI, or placebo. Spirometry, specific airway conductance, and lung volumes were measured at the beginning and at the end of each treatment period from predose to 4 h postdose. A 6-min walking test was carried out 4 h after the first and the last dose, with dyspnea assessed by Borg scale. Safety was assessed through adverse events monitoring electrocardiography and vital signs. RESULTS: The two formulations of formoterol were significantly superior to placebo but not different from each other in increasing 1-sec forced expiratory volume, specific airway conductance, inspiratory capacity, and inspiratory-to-total lung capacity ratio. The two active treatments were also equivalent and superior to placebo in reducing dyspnea at rest and on exertion. No differences in terms of safety between the two active forms and placebo were detected. CONCLUSIONS: Formoterol given with chlorine-free pMDI was equivalent to DPI in reducing airway obstruction and lung hyperinflation in COPD patients. Both formoterol formulations confirmed the good safety profile similar to placebo.