Eliana S. Mendes

Comparative bronchial vasoconstrictive efficacy of inhaled glucocorticosteroids

The vasoconstrictive efficacies of glucocorticosteroids (GS) are usually compared by the McKenzie skin-blanching test and taken as an index of relative potency. The rationale for the present study was to transpose the McKenzie test to the airway and to compare the airway vascular effects of three inhaled GS: beclomethasone dipropionate (BDP), fluticasone propionate (FP) and budesonide (BUD), in healthy subjects and patients with mild stable asthma. A soluble, inert gas-uptake method was used to measure airway blood flow (Qaw). Baseline mean±sd Qaw normalised for anatomical dead space was 53.1±1.4 µL·min−1·mL−1 in healthy subjects (n=10) and 67.8±3 µL·min−1·mL−1 in asthmatics (n=10). All GS caused a transient decrease in Qaw. The magnitude of the vasoconstriction was greater in asthmatics. The relative vasoconstrictive effect of BDP, FP and BUD was 1, 1.9, and 2.7, respectively, in asthmatics and 1, 3.3 and 3.0, respectively, in healthy subjects, as assessed by the dose required to decrease Qaw by 20% from the baseline, 30-min postdrug inhalation. Therefore, measuring airway blood flow may be a useful, site-specific parameter to assess the tissue bioavailability and vasoconstrictive efficacy of inhaled glucocorticosteroids.

Pulmonary disease and age at immigration among Hispanics: Results from the Hispanic Community Health Study/Study of Latinos

RATIONALE Asthma has been reported to be more prevalent among Hispanics of Puerto Rican heritage than among other Hispanics and among Hispanics born in the United States or who immigrated as children than among those who came as adults; however, direct comparisons across Hispanic groups are lacking. OBJECTIVES To test whether asthma is more prevalent among Hispanics of Puerto Rican heritage than among other Hispanic groups, whether asthma is associated with age of immigration, and whether chronic obstructive pulmonary disease varies by heritage in a large, population-based cohort of Hispanics in the United States. METHODS The Hispanic Community Health Study/Study of Latinos researchers recruited a population-based probability sample of 16,415 Hispanics/Latinos, 18-74 years of age, in New York City, Chicago, Miami, and San Diego. Participants self-reported Puerto Rican, Cuban, Dominican, Mexican, Central American, or South American heritage; birthplace; and, if relevant, age at immigration. A respiratory questionnaire and standardized spirometry were performed with post-bronchodilator measures for those with airflow limitation. MEASUREMENTS AND MAIN RESULTS The prevalence of physician-diagnosed asthma among Puerto Ricans (36.5%; 95% confidence interval, 33.6-39.5%) was higher than among other Hispanics (odds ratio, 3.9; 95% confidence interval, 3.3-4.6). Hispanics who were born in the mainland United States or had immigrated as children had a higher asthma prevalence than those who had immigrated as adults (19.6, 19.4, and 14.1%, respectively; P < 0.001). Current asthma, bronchodilator responsiveness, and wheeze followed similar patterns. Chronic obstructive pulmonary disease prevalence was higher among Puerto Ricans (14.1%) and Cubans (9.8%) than among other Hispanics (<6.0%), but it did not vary across Hispanic heritages after adjustment for smoking and prior asthma (P = 0.22), by country of birth, or by age at immigration. CONCLUSIONS Asthma was more prevalent among Puerto Ricans, other Hispanics born in the United States, and those who had immigrated as children than among other Hispanics. In contrast, the higher prevalence of chronic obstructive pulmonary disease among Puerto Ricans and Cubans was largely reflective of differential smoking patterns and asthma.

Feasibility of Shortening Respiratory Isolation with a Single Sputum Nucleic Acid Amplification Test

RATIONALE Serial smear analysis to guide respiratory isolation (RI) of patients with suspected tuberculosis (TB), the majority of whom will be found not to have TB, leads to expensive and unnecessary isolation, and may potentially result in decreased vigilance of subjects with respiratory compromise. OBJECTIVES To compare the performance of a single first-sputum, Mycobacterium tuberculosis-specific nucleic acid amplification (NAA) test with three sputum smears for assessing the need for RI. METHODS Prospective evaluation of 493 patients with suspected TB (74% HIV positive) admitted to RI in a major county hospital in the United States, who had at least three sputum smears and material available from the first sample for additional NAA testing. MEASUREMENTS AND MAIN RESULTS Accuracy of the first sputum NAA result and serial smears for identifying patients with potentially infectious TB who truly require RI was determined. Forty-six patients (9.3%) had TB confirmed by culture. First-sputum NAA test detected all patients with TB who had a positive smear (n = 35), even when the first of the three specimens was smear negative. In addition, when compared with serial smears, the first-sputum NAA had a higher sensitivity (0.87; 95% confidence interval [CI], 0.74-0.95) and specificity (1.0) in the detection of subjects with positive M. tuberculosis cultures (smear sensitivity, 0.76; 95% CI, 0.61-0.87; and specificity, 0.96; 95% CI, 0.94-0.98). CONCLUSIONS A single first-sputum NAA testing can rapidly and accurately identify the subset of patients with suspected TB who require RI according to serial sputum smears. Its potential use to shorten RI time does not preclude the need to obtain subsequent specimens for culture.

Airway endothelial dysfunction in asthma and chronic obstructive pulmonary disease: a challenge for future research.

Endothelial dysfunction in the extrapulmonary circulation has been linked to cardiovascular disease. Recent investigations have revealed that in the airway circulation, cigarette smoking, chronic obstructive pulmonary disease (COPD), and asthma are also accompanied by endothelial dysfunction. Inhaled glucocorticosteroids can partially or fully restore normal endothelium-dependent vasodilation in these conditions, thereby identifying the airway endothelium as a novel therapeutic target in the treatment of airway disease. The role of the defective endothelium-dependent vasodilation in the pathophysiology in asthma and COPD is still subject to speculation. However, there appears to be an association between COPD and extrapulmonary vascular dysfunction, and the possibility exists that the use of inhaled glucocorticosteroids has a beneficial effect on cardiovascular disease in COPD as suggested by database studies showing that inhaled glucocorticosteroids reduce the incidence of nonfatal and fatal cardiovascular events in COPD.

Effect of inhaled racemic and (R)-albuterol on airway vascular smooth muscle tone in healthy and asthmatic subjects

AbstractAlthough the relative effect of racemic and (R)-albuterol on airway smooth muscle tone have been investigated in patients with airflow obstruction, the comparative effectiveness of these drugs in relaxing airway vascular smooth muscle is unknown. Therefore, we determined the actions of inhaled racemic and (R)-albuterol on airway mucosal blood flow ( ) normalized for anatomic dead space as an index of airway vascular smooth muscle tone in 11 healthy subjects and 10 subjects with mild asthma. We also monitored the forced expiratory volume in 1 second (FEV1) as an index of airway smooth muscle tone. Mean ± SE baseline was 43.1 ± 1.5 µl.min−1.ml−1 in healthy subjects and 53.4 ± 2.1 µl.min−1.ml−1 in asthmatic subjects (p < 0.01). The corresponding values for FEV1 were 95.6 ± 1.4 and 86.8 ± 2.5% respectively, of predicted (p = 0.01). Racemic and (R)-albuterol caused a transient, dose-dependent increase of in healthy, but not in asthmatic subjects; the responses were not different between the two drugs. The FEV1 tended to increase more in asthmatics than in healthy subjects, again without a difference between the two drugs. These results show that racemic and (R)-albuterol have comparable effects on airway vascular smooth muscle and suggest that the blunted airway vascular smooth muscle response to albuterol in asthmatics is not related to (S)-albuterol.

Effect of an inhaled glucocorticoid on endothelial function in healthy smokers

Cigarette smoking is associated with attenuated endothelium-dependent vasodilation (endothelial dysfunction) in the systemic circulation, including the airway circulation. We wished to determine whether an inhaled corticosteroid could restore endothelial function in the airway of lung-healthy current smokers, ex-smokers, and nonsmokers. We measured baseline airway blood flow (Qaw) and Qaw reactivity to inhaled albuterol as an index of endothelium-dependent vasodilation and to sublingual nitroglycerin as an index of endothelium-independent vasodilation in lung-healthy current smokers, ex-smokers, and nonsmokers. Current smokers were then treated with inhaled fluticasone for 3 wk, and all measurements were repeated after fluticasone treatment and after a subsequent 3-wk fluticasone washout period. Baseline mean Qaw and endothelium-independent Qaw reactivity were similar in the three groups. Mean endothelium-dependent Qaw reactivity was 49.5% in nonsmokers, 42.7% in ex-smokers, and 10.8% in current smokers (P < 0.05 vs. nonsmokers). In current smokers, mean baseline Qaw was unchanged after fluticasone treatment, but endothelium-dependent Qaw reactivity significantly increased to 34.9%. Qaw reactivity was again blunted after fluticasone washout. Endothelial dysfunction, as assessed by vascular reactivity, can be corrected with an inhaled corticosteroid in the airway of lung-healthy current smokers. This proof of concept can serve as the basis for future clinical investigations on the effect of glucocorticoids on endothelial function in smokers.

Acute Effect of an Inhaled Glucocorticosteroid on Albuterol-Induced Bronchodilation in Patients With Moderately Severe Asthma

BACKGROUND We have previously shown that in patients with asthma a single dose of an inhaled glucocorticosteroid (ICS) acutely potentiates inhaled albuterol-induced airway vascular smooth muscle relaxation through a nongenomic action. An effect on airway smooth muscle was not seen, presumably because the patients had normal lung function. The purpose of the present study was to conduct a similar study in patients with asthma with airflow obstruction to determine if an ICS could acutely also potentiate albuterol-induced airway smooth muscle relaxation in them. METHODS In 15 adult patients with asthma (mean ± SE baseline FEV1, 62% ± 3%), the response to inhaled albuterol (180 μg) was assessed by determining the change in FEV1 (ΔFEV1) for airway smooth muscle and in airway blood flow (ΔQaw) for airway vascular smooth muscle measured 15 min after drug inhalation. Using a double-blind design, the patients inhaled a single dose of the ICS mometasone (400 μg) or placebo simultaneously with or 30 min before albuterol inhalation. RESULTS After simultaneous drug administration, mean ΔFEV1 was 0.20 ± 0.05 L (10%) after placebo and 0.32 ± 0.04 L (19%) after mometasone (P < .05); mean ΔQaw was -2% after placebo and 30% after mometasone (P < .005). When mometasone or placebo was administered 30 min before albuterol, there was a lesser and insignificant difference in ΔFEV1 between the two treatments, whereas the difference in ΔQaw remained significant. CONCLUSIONS This pilot study showed that in adult patients with asthma with airflow obstruction, a single standard dose of an ICS can acutely increase the FEV1 response to a standard dose of inhaled albuterol administered simultaneously. The associated potentiation of albuterol-induced vasodilation in the airway was of greater magnitude and retained when the ICS was administered 30 min before albuterol. The clinical significance of this observation will have to be established by a study involving a larger patient cohort. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT01210170; URL: www.clinicaltrials.gov.

Acute Effects of Salmeterol and Fluticasone Propionate Alone and in Combination on Airway Blood Flow in Patients With Asthma

BACKGROUND The airway contains airway smooth muscle and airway vascular smooth muscle. The acute effects of inhaled long-acting β(2)-adrenergic agonists (LABAs) alone, or in combination with an inhaled glucocorticoid (ICS), on airway smooth muscle tone in asthma are known; however, to the best of our knowledge, their effect on airway vascular smooth muscle tone has not been investigated previously. The objective of this study was to investigate the immediate effects of a LABA and an ICS alone and in combination on airway blood flow (Qaw) as an index of airway vascular smooth muscle tone in patients with stable asthma. METHODS Fourteen subjects with moderate asthma inhaled single doses of salmeterol (50 μg), fluticasone propionate (250 μg), salmeterol/fluticasone propionate (50/250 μg), or placebo; Qaw was measured before and serially for 240 min after drug administration. RESULTS Mean Qaw increased after salmeterol and salmeterol/fluticasone propionate, with peaks at 60 min of 34% and 40%, respectively, and returned to baseline by 240 min after inhalation. Fluticasone propionate alone caused a transient decrease in mean Qaw. The maximal changes in Qaw, which occurred at different times, were 60% for salmeterol, 67% for salmeterol/fluticasone propionate, and -19% for fluticasone propionate (P < .05 vs placebo for all). CONCLUSIONS The LABA salmeterol has an acute vasodilator action on the airway of subjects with stable asthma. The addition of fluticasone propionate, which by itself causes vasoconstriction, does not attenuate the salmeterol-induced vasodilation, suggesting that fluticasone propionate potentiates the vasodilator effect of salmeterol. The vasodilation could be of clinical benefit by promoting the vascular clearance of inflammatory mediators including spasmogens from the airway. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT01231230; URL: www.clinicaltrials.gov.

Exercise-related change in airway blood flow in humans: Relationship to changes in cardiac output and ventilation

This study examined the relationship between airway blood flow (Q(aw)), ventilation (V(E)) and cardiac output (Q(tot)) during exercise in healthy humans (n=12, mean age 34+/-11 yr). Q(aw) was estimated from the uptake of the soluble gas dimethyl ether while V(E) and Q(tot) were measured using open circuit spirometry. Measurements were made prior to and during exercise at 34+/-5 W (Load 1) and 68+/-10 W (Load 2) and following the cessation of exercise (recovery). Q(aw) increased in a stepwise fashion (P<0.05) from rest (52.8+/-19.5 microl min(-1) ml(-1)) to exercise at Load 1 (67.0+/-20.3 microl min(-1) ml(-1)) and Load 2 (84.0+/-22.9 microl min(-1) ml(-1)) before returning to pre-exercise levels in recovery (51.7+/-13.2 microl min(-1) ml(-1)). Q(aw) was positively correlated with both Q(tot) (r=0.58, P<0.01) and V(E) (r=0.50, P<0.01). These results demonstrate that the increase in Q(aw) is linked to an exercise related increase in both Q(tot) and V(E) and may be necessary to prevent excessive airway cooling and drying.

Acute Effect of Cigarette Smoke and Nicotine on Airway Blood Flow and Airflow in Healthy Smokers

Cigarette smoke contains irritants and vasoactive substances. We wanted to determine the effect of smoking a cigarette and of nasally or orally inhaled nicotine on airway blood flow (Qaw) and airflow in smokers. In ten healthy current smokers, Qaw, FEV1, and FEF25–75 were measured before and at 5, 30, and 180 min after smoking a cigarette. The effects of systemic nicotine using a nicotine nasal spray and local nicotine using a nicotine inhaler were also studied. Mean (± SE) Qaw increased by 81% ± 16% (p = 0.03) 5 min after smoking a cigarette and was no longer different from baseline at 30 and 180 min. Nicotine nasal spray and nicotine oral inhaler had no effect on Qaw. FEV1 and FEF25-75 remained unchanged after smoking a cigarette and after local or systemic nicotine administration. Smoking a cigarette is followed by a transient increase in airway blood flow but no changes in airflow. Nicotine, at the rate and dose provided by the nasal spray (systemic action) and oral inhaler (local and systemic action), does not appear to be involved in the Qaw change, suggesting a pharmacologic or nonspecific irritant effect of other cigarette smoke constituents.