Changes in airflow obstruction and oxygen saturation in response to exercise and bronchodilators in cystic fibrosis

The airway response to exercise and inhaled terbutaline was assessed in 25 patients with cystic fibrosis (CF), seeking evidence for the possible deleterious effects of bronchial muscle relaxation. We postulated that "early" and "late" flows, taken from the full maximum expiratory flow volume curve, might move paradoxically in patients with unstable airways. Oxygen saturation was measured continuously; desaturation occurred early in exercise with partial recovery thereafter. This was unrelated to changes in expiratory airflow measurements. Both during and after exercise, and after inhaled bronchodilator, changes in expiratory airflow measurements were strikingly variable. Changes in individual measurements should be interpreted in relationship to the within-subject variability of the test in patients with CF. During exercise, there was a significant increase in mean FEV1; this was most marked in patients with worst lung function. Two patients (both with severe lung disease) showed paradoxical changes in early and late flows. After exercise, only two patients showed the asthmatic pattern of postexercise bronchoconstriction. After inhaled bronchodilator, the group as a whole showed small but statistically significant increases in expiratory airflow measurements. Those with highest baseline FEV1 had the greatest bronchodilator response; this is the opposite of the pattern observed in asthma. Paradox did not occur after bronchodilators and only one patient showed a significant fall in late expiratory airflow. This pattern of expiratory airflow changes is compatible with the concept of airway instability in which any beneficial effects of bronchial tone reduction are canceled out by the effects of compression of damaged airways rendered more compliant by loss of bronchial wall tone. We did not observe any clinically important deleterious effects from this mechanism.     

Assessment of airway function in young children with asthma: comparison of spirometry, interrupter technique, and tidal flow by inductance plethsmography

The assessment of airway function in young children requires adaptation of techniques designed for adults and/or application of techniques that do not require complex respiratory maneuvers. We sought to assess two methods of measuring airway function: time to peak expiratory flows as a ratio of expiratory time (T(PTEF)/T(E)), derived from respiratory inductance plethysmography, and total respiratory resistance by the interrupter technique (Rint), both obtained during quiet tidal breathing. Both techniques were referenced to FEV1 and flow at 50% expired volume (FEF50) from conventional spirometry in 30 children aged 4-8 years (median age, 6.9; range, 4.5-8.5 years) with a physician diagnosis of asthma and who were able to perform FEV1 with a repeatability of at least 8%. T(PTEF)/T(E) and Rint were performed in random order followed by spirometry, in order to reduce the possible effects of pulmonary stretch on tidal breathing measures. Coefficients of variation (CV) and mean absolute change/baseline standard deviation were derived for each measurement. Baseline FEV1 did not correlate significantly with T(PTEF)/T(E) (r = 0.025), but did correlate with Rint (r = 0.737, P < 0.001); respective relationships for change after bronchodilator were r = 0.09 (ns) and r = 0.64 (P < 0.001). FEF50 also correlated significantly with Rint (R = 0.769, P < 0.001) but not with T(PTEF)/T(E). FEV1 and FEF50 both increased postbronchodilator, with respective mean changes of 11.4% and 28% (P < 0.001), while Rint decreased by 24.3% (P < 0.001). No significant changes were noted for T(PTEF)/T(E). T(PTEF)/T(E) derived from inductance plethysmography does not detect mild airway obstruction or modest changes in airway caliber following bronchodilator in young children with asthma. The interrupter technique may have a role in assessing baseline airway function and response to therapy in children unable to perform reliable spirometry, and/or when the investigator wishes to avoid the possible influence of forced maneuvers on airway tone.     

Airway reactivity is a determinant of bronchodilator responsiveness after methacholine-induced bronchoconstriction.

Airway hyperresponsiveness (AHR) is one of the characteristics of asthma and a risk factor for persistent airflow limitation. Poor response to bronchodilator may be a cause of persistent airflow limitation. Multiple factors may determine bronchodilator responsiveness, including airway reactivity to nonspecific bronchoconstrictive agents. If patients with AHR have poor bronchodilator responsiveness, then it could be a potential mechanism for asthma and persistent airflow limitation in these patients. The objective of this study is to assess the relationship between airway reactivity to methacholine and responsiveness to beta-agonist and beta-agonist/anticholinergic combination in a large subject population. A retrospective data analysis was undertaken of 764 consecutive subjects with > or = 20% reduction in forced expiratory volume during the first second of exhalation from total lung capacity (FEV1) after < or = 189 cumulative units of methacholine. The first 382 subjects received 3 inhalations of metaproterenol and the second 382 subjects received 3 inhalations of albuterol and ipratropium combination after > or = 20% reduction in FEV1. Bronchodilator responsiveness was measured as the percent increase in FEV1 after the treatment. Airway reactivity was assessed as the log10 of methacholine dose response slope. In a simple linear regression model, airway reactivity was significantly related to bronchodilator responsiveness. The coefficient of determination (r2) was 0.15 for the whole groups; 0.14 for metaproterenol group and 0.18 for albuterol/ipratropium combination group (all p<0.0001). The regression coefficient (beta) was 14.0 for the whole group; 14.8 and 13.2, respectively, for the two bronchodilator groups. Airway reactivity to methacholine is a determinant of airway responsiveness to both beta-agonist and beta-agonist/anticholinergic combination. Subjects with higher airway reactivity have higher bronchodilator responsiveness.     

Radiological and functional changes over 3 years in young children with cystic fibrosis.

The aim of the present study was to evaluate airway disease progression assessed by chest radiology, expiratory interrupter resistance (Rint,exp) and spirometry in young children with cystic fibrosis (CF) over a 3-yr period. Two chest radiographs combined with two R(int,exp) measurements were performed with a 3-yr interval in 21 preschool children (age (mean+/-sd) 3.2+/-0.9 yrs) and 30 schoolchildren with CF (age 7.2+/-1.9 yrs). Chest radiographs were scored using five different CF scoring systems and Rint,exp measurements were expressed as height-adjusted Z-scores. Spirometry was assessed in schoolchildren and the results were expressed as a percentage of predicted values. Chest radiograph scores worsened significantly over the 3-yr period and a tendency towards more pronounced changes was observed, especially for the Wisconsin score, in preschool children. Most preschool and schoolchildren had Rint,exp Z-scores within the normal range at start and follow-up, and the annual change in Rint,exp Z-score was not significant. In schoolchildren, only the forced expiratory volume in one second as a percentage of forced vital capacity declined significantly during the study period. In summary, in young children with cystic fibrosis, chest radiograph scores worsen significantly over time even while lung function remains stable.     

Exhaled nitric oxide, serum ECP and airway responsiveness in mild asthmatic children.

The purpose of the present study was to assess the possible relationships between exhaled nitric oxide (ENO), a circulating marker of eosinophil activation, serum eosinophil cationic protein (SECP), level of airway responsiveness to methacholine and lung function in asthmatic children, as well as to compare these markers between children with and without inhaled steroid therapy. In a cross-sectional study ENO, SECP and bronchial hyperresponsiveness to methacholine were evaluated in a group of 57 asthmatic children (21 without and 36 with regulator inhaled steroid therapy; aged 6-13 yrs). ENO was significantly lower in steroid treated children (p<0.01). No significant differences between steroid treated and untreated children were observed for the provocative concentration of methacholine causing a 20% fall in forced expiratory volume in one second (FEV1; PC20), SECP and FEV1. In the whole study population significant increase correlations were observed between PC20 and SECP (r=-0.329, p=0.013) and between ENO and FEV1% of predicted (r=-0.348, p<0.01). In the group not receiving inhaled steroids the inverse relationship between PC20 and SECP was more evident (r=-0.581, p<0.001). In the steroid-treated group a significant inverse relationship was observed between ENO and FEV1 (r=-0.426, p=0.0011). The level of exhaled nitric oxide and the relationships between lung function, bronchial reactivity and markers of inflammation are different between steroid-treated and untreated asthmatic children. This has implications for the monitoring of asthma in childhood.     

Airway Reactivity Is a Determinant of Bronchodilator Responsiveness After Methacholine‐induced Bronchoconstriction

Airway hyperresponsiveness (AHR) is one of the characteristics of asthma and a risk factor for persistent airflow limitation. Poor response to bronchodilator may be a cause of persistent airflow limitation. Multiple factors may determine bronchodilator responsiveness, including airway reactivity to nonspecific bronchoconstrictive agents. If patients with AHR have poor bronchodilator responsiveness, then it could be a potential mechanism for asthma and persistent airflow limitation in these patients. The objective of this study is to assess the relationship between airway reactivity to methacholine and responsiveness to beta‐agonist and beta‐agonist/anticholinergic combination in a large subject population. A retrospective data analysis was undertaken of 764 consecutive subjects with ≥ 20% reduction in forced expiratory volume during the first second of exhalation from total lung capacity (FEV1) after ≤ 189 cumulative units of methacholine. The first 382 subjects received 3 inhalations of metaproterenol and the second 382 subjects received 3 inhalations of albuterol and ipratropium combination after ≥ 20% reduction in FEV1. Bronchodilator responsiveness was measured as the percent increase in FEV1 after the treatment. Airway reactivity was assessed as the log10 of methacholine dose response slope. In a simple linear regression model, airway reactivity was significantly related to bronchodilator responsiveness. The coefficient of determination (r²) was 0.15 for the whole groups; 0.14 for metaproterenol group and 0.18 for albuterol/ipratropium combination group (all p < 0.0001). The regression coefficient (β) was 14.0 for the whole group; 14.8 and 13.2, respectively, for the two bronchodilator groups. Airway reactivity to methacholine is a determinant of airway responsiveness to both beta‐agonist and beta‐agonist/anticholinergic combination. Subjects with higher airway reactivity have higher bronchodilator responsiveness.     

Beta 2 adrenergic receptor polymorphisms in cystic fibrosis

There has been a recent emphasis on identifying modifier genes that influence the severity of cystic fibrosis (CF) lung disease. The beta-2-adrenergic receptor is expressed on airway smooth muscle, is the target for inhaled beta agonists, and has several common polymorphisms in its gene, ADRB2. Polymorphisms changing glycine to arginine or glutamate to glutamine in codons 16 and 27, respectively, were associated with differences in clinical response to inhaled beta agonists in individuals with asthma. We compared acute airway responsiveness and 5-year decline in pulmonary function in CF patients with different ADRB2 genotypes. One hundred and six subjects performed spirometry before and after the administration of an inhaled bronchodilator, and had ADRB2 genotype determined for codons 16 and 27. Comparing the percent change in FEV(1) and FEF(25-75) continuously revealed differences in the degree of airway responsiveness to bronchodilator between ADRB2-genotyped groups. However, there was no significant relationship between the ADRB2 genotype at positions 16 and 27 and bronchodilator response when defined as 12% improvement in FEV(1). Five-year decline in percent predicted FEV(1) showed no association with ADRB2 genotype. These data are consistent with variants of the ADRB2 gene having different responses to bronchodilator, but the long-term effects, if any, are not apparent over a 5-year period.     

Diagnostic value of negative expiratory pressure for airway hyperreactivity

STUDY OBJECTIVES: To examine the value of negative expiratory pressure (NEP) in the assessment of methacholine bronchoprovocation testing (BPT). DESIGN: Prospective, observational study. SETTING: Pulmonary function laboratory in a university hospital. PARTICIPANTS: Fifty-nine patients with chronic cough referred from outpatient clinics for methacholine BPT. METHODS: Each subject inhaled successive doubling concentrations of methacholine (from 0.049 to 25 mg/mL) until the FEV(1) decreased for > 20% or the maximum concentration of methacholine was inhaled. NEP was measured in the sitting position during tidal breathing before and after methacholine BPT. The FEV(1) and forced oscillation airway resistance (Rrs) and interrupter airway resistance (Rint) were also obtained simultaneously. A positive BPT result was defined as a fall in FEV(1) > or = 20%. RESULT: At baseline, only five patients had expiratory flow limitation as demonstrated by NEP (EFL-N). There were 39 patients with positive BPT results, and the other 20 patients had negative results. Among the BPT-positive patients, only 13 patients (33.3%) had EFL-N after methacholine challenge. The sensitivity indexes (absolute change/SD) of FEV(1), NEP, Rrs, and Rint were 16.0 +/- 9.6%, 1.1 +/- 1.6%, 3.8 +/- 4.5%, and 5.89 +/- 4.4% (mean +/- SD), respectively. The percentage changes in FEV(1) in BPT-positive patients correlated with the percentage changes in Rrs (r = 0.419, p = 0.008) and only marginally with the percentage changes in Rint (r = 0.307, p = 0.058), but not with the changes in EFL-N (r = 0.048, p = 0.77). CONCLUSION: These data suggest that NEP at sitting position is not sensitive in the assessment of methacholine bronchoprovocation as compared to FEV(1) and airway resistance measurements.     

Pulmonary function tests in preschool children with cystic fibrosis

Pulmonary function tests have rarely been assessed in preschool children with cystic fibrosis (CF). The objective of this multicenter study was to compare pulmonary function in 39 preschool children with CF (height, 90-130 cm; 16 homozygous Delta F508) and in 79 healthy control children. Functional residual capacity (helium dilution technique) and expiratory interrupter resistance (Rint(exp)) (interrupter technique) were measured. As compared with control children, children with CF had significantly higher Rint(exp), expressed as absolute values and as Z-scores (1.05 +/- 0.36 versus 0.80 +/- 0.20 kPa.L(-1). second, p < 0.0001; and 1.31 +/- 1.72 versus 0.19 +/- 0.97, p < 0.0001), and significantly lower specific expiratory interrupter conductance (1.29 +/- 0.34 versus 1.63 +/- 0.43 kPa(-1). second, p < 0.0001). The effect of the bronchodilator salbutamol on Rint(exp) was not significantly different between children with CF and control children. Rint(exp) Z-scores were significantly higher in children with CF who were exposed to passive smoke (n = 8) (p < 0.03). Children with CF and with a history of respiratory symptoms (n = 31) had significantly higher functional residual capacity Z-scores (p < 0.02) and lower specific expiratory interrupter conductance Z-scores (p < 0.04). Genotype did not influence the data. We conclude that Rint(exp) and functional residual capacity measurements may help to follow young children with CF who are unable to perform reproducible forced expiratory maneuvers.     

Comparison of the forced oscillation technique and the interrupter technique for assessing airway obstruction and its reversibility in children

The forced oscillation technique (FOT) and interrupter technique are particularly attractive for pediatric use as they require only passive cooperation from the patient. We compared the sensitivity and specificity of these methods for detecting airway obstruction and its reversibility in 118 children (3-16 yr) with asthma or chronic nocturnal cough. FOT (R(0) and R(16)) and interruption (Rint) parameters were measured at baseline and after bronchodilator inhalation (n = 94). Rint was significantly lower than R(0), especially in children with high baseline values. Baseline parameters were normalized for height and weight [R(SD)]. In children able to perform forced expiratory maneuvers (n = 93), the best discrimination between those with baseline FEV(1) < 80% or > or = 80% of predicted values was obtained with R(0)(SD). At a specificity of 80%, R(0)(SD) yielded 66% sensitivity, whereas Rint(SD) yielded only 33% sensitivity. Similarly, postbronchodilator changes in R(0)(SD) [DeltaR(0)(SD)] yielded the best discrimination between children with and without significant reversibility in FEV(1). At a specificity of 80%, DeltaR(0)(SD) yielded 67% sensitivity and DeltaRint(SD) yielded 58% sensitivity. In children unable to perform forced expiratory maneuvers (n = 25), FOT, contrary to the interrupter technique, clearly identified a subgroup of young children with high resistance values at baseline, which returned to normal after bronchodilation. We conclude that, in asthmatic children over 3 yr old, FOT measurements provide a more reliable evaluation of bronchial obstruction and its reversibility compared with the interrupter technique, especially in young children with high baseline values.     

Bronchodilators increase airway instability in cystic fibrosis

Supramaximal flow transients of partial expiratory flow-volume curves are caused by a rapidly emptying compartment. By superimposing a maximal and a series of partial expiratory flow-volume curves, the volume of the flow transient equivalent for the maximal curve was estimated (volume of airway contribution = VACMEFV). This flow transient equivalent is caused by an extra dead space, created in the large airways by a full inspiration. In 18 children with cystic fibrosis (CF), routine pulmonary functions and VACMEFV were measured before and after bronchodilator medication. Baseline VACMEFV correlated directly with the curvilinearity of the flow-volume curve and inversely with the clinical and radiologic score. Significantly, bronchodilator medication improved FVC, FEV1, FEF25-75, VC, PEF, Raw, and also VACMEFV. In 6 children, VEmax25 increased as a result of apparent peripheral bronchodilation. In 3 others, end-expiratory flow increased slightly but the expanded VACMEFV included the measuring point invalidating the measurement. In the remaining 9 patients, VEmax25 decreased after bronchodilator. As an apparent discrepancy, FEV1, FVC, PEF, VC, FEF25-75 increased, and Raw decreased in 4 to 9 patients. The volumes and flow rates measured early in forced expiration and the end-expiratory flow behaved differently because VACMEFV expanded beyond the measuring points of early expiratory and mid-expiratory flow rates. As the bronchodilator rendered the compliant large airways still more distensible, the amount of air emptied from the dead space in early forced expiration increased. Simultaneously, end-expiratory flow decreased because of enhanced airway compression.(ABSTRACT TRUNCATED AT 250 WORDS)     

Reference values of the provocative concentrations of methacholine that cause 6% and 20% changes in forced expiratory volume in one second in a normal population

The provocative concentrations of inhaled methacholine that cause 6% (PC6) and 20% (PC20) falls in forced expiratory volume in one second (FEV1) were assessed in a population of 100 nonsmoking persons, equally distributed for sex, who ranged uniformly from 20 to 60 yr of age. These subjects had no respiratory symptoms, rhinitis, atopic history, or familial history of asthma. Single twofold dilutions of methacholine from 2 to 128 mg/ml were used; 81 and 34 subjects, respectively, showed PC6 and PC20 values less than 128 mg/ml. Eight subjects had PC20 values less than 16 mg/ml. In these subjects, the test had a good reproducibility (r = 0.92) when we repeated it, and serial measurements of peak expiratory flow rates did not suggest asthma. The fact that PC6 was related, although loosely, to baseline FEV, FEV/FVC, and forced expiratory flow during the middle half of the FVC (FEF) and that 4 of the 8 subjects with PC20 values less than 16 mg/ml had lower values of FEF might suggest that responsiveness to methacholine is partially linked with baseline airway caliber.     

Interrupter technique versus plethysmography for measurement of respiratory resistance in children with asthma or cystic fibrosis

The purpose of the present study was to compare measurements of respiratory system resistance by the interrupter method (Rrsint) with those of airway resistance by plethysmography (Raw) in nonobstructed children with asthma or cystic fibrosis (ratio of forced expiratory volume in 1 sec to vital capacity, FEV(1)/VC >/=80% with a forced expiratory flow rate between 25-75% of forced vital capacity, FEF(25-75) >/=75% of normal values) and in obstructed children with the same diseases (FEV(1)/VC <80% and/or FEF(25-75) <75% of normal values). Eighty-one children (47 asthmatics and 34 suffering from cystic fibrosis) aged 5-18 years (mean 11.2 +/- SD 3.4 years) were included in the study. For the overall group, we observed generally lower values for Raw (4.7 +/- 2. 8 cmH(2)O.L(-).s) than for Rrsint20 (extrapolation of the mouth pressure during occlusion to 40 ms after interruption) (5.6 +/- 1.7 cmH(2)O.L(-1).s) (P < 0.02), or for Rrsint40 (extrapolation of the mouth pressure during occlusion to 60 ms after interruption) (6.6 +/- 2.2 cmH(2)O.L(-1).s) (P < 0.001), but there was no difference between Rrsint20 and Raw in the obstructed subgroup. Moreover, we observed a correlation between the difference (Rrsint20 - Raw) expressed in percentage of predicted values and the degree of obstruction estimated by FEV(1)/VC (r = 0.56, P < 0.001). The differences between the specific resistances (sRrsint20 - sRaw, sRrsint40 - sRaw) were also correlated with the severity of the obstruction (r = 0.65, P < 0.001 and r = 0.57, P < 0.001, respectively). We observed also that the tendency to underestimate resistance by Rrsint in obstructed children was not the same in children with asthma and cystic fibrosis. We conclude that the tendency of Rrsint, as measured with our method, to underestimate airway obstruction appears to increase in proportion to the severity of the airway obstruction.     

Home spirometry and asthma severity in children.

The usefulness of peak expiratory flow monitoring is disputed because of the unreliability of written peak flow diaries. The aim of the present study was to examine the relationship of peak flow and forced expiratory volume in one second (FEV1) variation to other estimates of asthma severity in children, using an electronic home spirometer with automatic data storage. Over a 3-month period, 36 children with mild-to-moderate persistent asthma recorded peak flow and FEV1 electronically twice daily and noted an asthma severity score in a written diary. Bronchial responsiveness was assessed at the beginning and bronchodilator response and asthma-specific quality of life at the end of the study. Variations in peak flow correlated significantly but weakly to bronchial responsiveness and bronchodilator response, but not to the asthma severity score or quality-of-life scores. Within-individual correlations between asthma severity scores and home spirometry indices and between peak flow and FEV1 were highly variable. In conclusion, variations in peak flow and forced expiratory volume in one second, obtained by home spirometry, show poor concordance with other indices of disease activity and with each other. This limits the usefulness of home spirometry in childhood asthma.     

Comparison between peak expiratory flow rate and forced expiratory volume in one second in the evaluation of children suspected to have asthma

This study was conducted to evaluate whether forced expiratory volume in 1 second (FEV1) for the diagnosis of bronchial reactivity by means of the free-running exercise test and bronchodilator inhalation, could be appropriately replaced by simple measurements of peak expiratory flow rate (PEFR) in children.We studied 108 referred symptomatic children (due to chronic cough or wheezing) suspected to have asthma aged 5-14y. Forced breathing spirometry and the "Mini-Wright peak flow meter" tests were recorded before and fifteen minutes after the challenge with free- running exercise or bronchodilator (Salbutamol) inhalation, regarding the baseline FEV1 value (FEV1> 80% considered as normal).There was a high correlation between PEFR and FEV1 (in absolute value and percent predicted) measured before and after bronchodilator inhalation test (r = 0.48, P = 0.05) in comparison to the values referred to free- running exercise test (r = 0.26, P = 0.01)."forced breathing spirometry" and "Mini-Wright peak flow" cannot be used interchangeably for diagnosing asthma, and PEFR measurement should remain a procedure for monitoring and following up the patients.     

Effects of respiratory timing and cheek support on resistance measurements, before and after bronchodilation in asthmatic children using the interrupter technique

The interrupter technique (Rint) is a noninvasive method for assessing respiratory resistance. The aims of this study were to assess whether upper airway support affects the measurement of Rint, if inspiratory or expiratory Rint were most reproducible, and which method of assessing Rint correlated best with spirometry results and was the most sensitive for identifying bronchodilator response. Twenty-four asthmatic children with a mean age of 10.3 years (range, 7-16 years) were included in the study. Rint measurements were obtained in inspiration and expiration with cheeks supported and unsupported. Spirometry was then performed. Rint and spirometry measurements were repeated after the inhalation of 600 mcg of salbutamol. The mean Rint supported inspiratory (0.708 KPa/l/sec) and expiratory (0.729 KPa/l/sec) values were significantly higher than the unsupported values (inspiratory, 0.622 KPa/l/sec; expiratory, 0.584 KPa/l/sec), P < 0.05 and P < 0.001, respectively. The reproducibility of Rint was not different whether cheeks were supported or not, or whether the measurements were carried out during inspiration or expiration. Cheek support improved the correlation with all the lung function results, both in inspiratory and expiratory measurements. The best correlations, however, were found for the inspiratory supported Rint results. The most sensitive method to ascertain bronchodilator response (BD) was the inspiratory supported Rint measurement, as 83.3% of children were identified as having a positive response to bronchodilator therapy as defined by a reduction of twice the coefficient of variation of the measurement. In conclusion, cheek support increases Rint but does not impact on reproducibility, though it improves the correlation with spirometric indices. Rint with cheek support on inspiration correlates best with spirometric indices and appears to be the most sensitive measure of response to bronchodilators.     

Inhaled Fluticasone and Salmeterol Suppress Eosinophilic Airway Inflammation in Chronic Obstructive Pulmonary Disease: Relations with Lung Function and Bronchodilator Reversibility

The aim of this study was to determine whether combined inhaled corticosteroids and long-acting β₂ agonists can suppress eosinophilic inflammation in chronic dostructive plumonary disease (COPD) and to investigate the association between the level of eosinophilia and the degree of bronchodilator reversibility. Sixty-two patients with stable COPD (forced expiratory volume in 1 [FEV₁] of 30%–70% predicted before bronchodilation) were enrolled from our outpatient clinic. Patients received inhaled fluticasone (100 μg)/salmeterol (50 μg) twice daily for two months. Lung function measurements, bronchodilator tests, and sputum induction were performed. The number of inflammatory cells and mediators, including interleukin-8 (IL-8), tumor necrosis factor-α (TNF-α), and eosinophilic cationic protein (ECP), were measured. Treatment with inhaled fluticasone and salmeterol significantly suppressed eosinophilic inflammation in COPD patients with sputum eosinophilia (mean 8.9% ± 2.0% vs. 1.6% ± 0.5%, p = 0.003), but insignificant differences in FEV₁ and FVC between patients with and without eosinophilia suggested that suppression of eosinophilic inflammation had no effect on FEV₁ or FVC. Reduction in the percentage of eosinophils was significantly correlated with decreased levels of ECP (r = 0.48, p < 0.001). Levels of neutrophils, IL-8, and TNF-α were not affected. Sputum eosinophilia was not related to the degree of bronchodilator reversibility. The degree of bronchodilator reversibility did not predict the increase in FEV₁ and FVC after treatment with inhaled corticosteroids/long-acting β₂ agonists. Suppression of eosinophilic inflammation and bronchodilator responsiveness indices were not correlated with clinical outcomes in COPD patients treated with inhaled corticosteroids/long-acting β₂ agonists. Diahn-Warng Perng and Cheng-Che Wu contributed equally to this work.     

Markers of airway inflammation and airway hyperresponsiveness in patients with well-controlled asthma.

In steroid-naive asthmatics, airway hyperresponsiveness correlates with noninvasive markers of airway inflammation. Whether this is also true in steroid-treated asthmatics, is unknown. In 31 stable asthmatics (mean age 45.4 yrs, range 22-69; 17 females) taking a median dose of 1,000 microg inhaled corticosteroids (ICS) per day (range 100-3,600 microg x day(-1)), airway responsiveness to the "direct" agent histamine and to the "indirect" agent mannitol, lung function (forced expiratory volume in one second (FEV1), forced vital capacity (FVC), peak expiratory flow (PEF)), exhaled nitric oxide (eNO), and number of inflammatory cells in induced sputum as a percentage of total cell count were measured. Of the 31 subjects, 16 were hyperresponsive to mannitol and 11 to histamine. The dose-response ratio (DRR: % fall in FEV1/cumulative dose) to both challenge tests was correlated (r=0.59, p=0.0004). However, DRR for histamine and DRR for mannitol were not related to basic lung function, eNO, per cent sputum eosinophils and ICS dose. In addition, NO was not related to basic lung function and per cent sputum eosinophils. In clinically well-controlled asthmatics taking inhaled corticosteroids, there is no relationship between markers of airway inflammation (such as exhaled nitric oxide and sputum eosinophils) and airway responsiveness to either direct (histamine) or indirect (mannitol) challenge. Airway hyperresponsiveness in clinically well-controlled asthmatics appears to be independent of eosinophilic airway inflammation.     

Determinants of bronchodilator responsiveness in patients with controlled asthma.

Short-term bronchodilator responsiveness to an inhaled ss 2 adrenergic agonist was assessed by changes in forced expiratory volume in 1 second (FEV(1)) in nonsmoking adults with controlled asthma (mild disease, 20 patients; moderate disease, 20 patients; severe disease, 18 patients). Responsiveness correlated significantly with age and with percent of predicted FEV(1) (%FEV(1)) except in patients with severe asthma, who showed significantly less responsiveness than others. Thus, responsiveness is closely associated with degree of airflow limitation in patients with controlled asthma and is significantly influenced by severity of disease and by aging.