Risk factors for airway remodeling in asthma manifested by a low postbronchodilator FEV1/vital capacity ratio: a longitudinal population study from childhood to adulthood

Airway remodeling may lead to irreversible loss of lung function in asthma. The impact of childhood asthma, airway responsiveness, atopy, and smoking on airway remodeling was investigated in a birth cohort studied longitudinally to age 26. A low postbronchodilator ratio of forced exhaled volume in 1 second (FEV1) to vital capacity (VC) at age 18 or 26 was used as a marker of airway remodeling. "Normal" study members with no history of asthma ever, no wheezing in the last year, and no smoking ever were used to determine sex- and age-specific reference values for this ratio. The lower limit of normal was defined as the mean ratio minus 1.96 standard deviation, delimiting the 2.5% of the normal population with the lowest FEV1/VC ratio. A low postbronchodilator FEV1/VC ratio was found in 7.4% and 6.4% of study members at ages 18 and age 26 and 4.6% at both assessments. Lung function was low throughout childhood in those with a consistently low postbronchodilator FEV1/VC ratio at both ages. Those with consistently low postbronchodilator ratios also showed a greater decline in the prebronchodilator FEV1/VC ratio from ages 9 to 26 compared with those with normal postbronchodilator ratios at both ages (males, -12% versus -6%, p < 0.0001; females, -10.5% versus -5.5%, p < 0.01). Asthma, male sex, airway hyperresponsiveness, and low lung function in childhood were each independently associated with a low postbronchodilator FEV1/VC ratio, which in turn was associated with an accelerated decline in lung function and decreased reversibility. These data suggest that airway remodeling in asthma, as manifested by impaired lung function, begins in childhood and continues into adult life.     

Effects of early intervention with inhaled budesonide on lung function in newly diagnosed asthma

STUDY OBJECTIVES: Asthmatic patients lose lung function faster than normal subjects. The effectiveness of early intervention with inhaled corticosteroids on this decline in lung function is not established in recent-onset disease. DESIGN: The Inhaled Steroid Treatment as Regular Therapy in Early Asthma study was a randomized, double-blind study in 7,165 patients (5 to 66 years old), with persistent asthma for < 2 years to determine whether early intervention with low-dose inhaled budesonide prevents severe asthma-related events and the decline in lung function. Patients received budesonide (200 mug qd for children < 11 years old and 400 mug qd for others) or placebo for 3 years in addition to usual asthma medications. RESULTS: Treatment with budesonide significantly improved prebronchodilator and postbronchodilator FEV(1) percentage of predicted and reduced the mean declines from baseline for postbronchodilator FEV(1) at 1 year and 3 years: - 0.62% and - 1.79% for budesonide and - 2.11% and - 2.68% for placebo, respectively (p < 0.001). The decline was more marked for male patients, active smokers, and patients > 18 years old, and the smallest treatment effects were in adolescents. CONCLUSIONS: Long-term, once-daily treatment with low-dose budesonide improved both prebronchodilator and postbronchodilator FEV(1) in patients with recent-onset, persistent asthma, and reduced the loss of lung function over time.     

Deficient alpha-1-antitrypsin phenotypes and persistent airflow limitation in severe asthma

BACKGROUND: Persistent airflow limitation is common among patients with severe asthma, but its pathogenesis has not been fully clarified. Severe alpha-1-antitrypsin (AAT) deficiency is a risk factor of chronic airflow limitation and emphysema, and partially deficient phenotypes have been associated with an accelerated decline in lung function. We hypothesized that partial deficiency of AAT (non-PiM AAT phenotype) is a risk factor of persistent airflow limitation in asthma. METHODS: In 122 patients with severe asthma (86 females; age (median (range)): 44.0 yr (18-75)) postbronchodilator FEV1 and FEV1/VC were measured and the AAT phenotype was determined. Persistent airflow limitation was defined as postbronchodilator FEV1 or FEV1/VC < 75% pred. with TLC > 75% pred. RESULTS: Six patients (4.9%) had a non-PiM phenotype (1 MF, 3 MS, 1 MZ and 1 SZ). Of the 58 patients with persistent airflow limitation only 1 patient (1.7%) had a non-PiM phenotype vs. 7.8% among the patients without persistent airflow limitation (P = 0.21). Postbronchodilator FEV1/VC (% pred.) was higher in the non-PiM patients than in the PiM patients (P = 0.02), the other lung function parameters were not different. Linear regression analysis showed no association between AAT phenotype and FEV1% predicted (P = 0.26). CONCLUSIONS: AAT heterozygoty does not seem to be an important risk factor of persistent airflow limitation in patients with asthma. Although confirmation by longitudinal follow-up studies with larger sample sizes is needed, these results suggest that routine assessment of the AAT phenotype is not indicated in asthmatic patients even if they exhibit fixed airflow limitation.     

Relationship between lung function and asthma symptoms in patients with difficult to control asthma.

Several studies have demonstrated a poor relationship between measures of asthma control and lung function in patients with asthma. We sought to examine this relationship in a cohort of difficult to control asthmatics attending a hospital outpatient clinic. FEV1 % and asthma control scores (ACSs) were measured at the first clinic visit and at a follow-up visit. A total of 59 patients took part in the study. At the initial visit, FEV1 % correlated with limitation of activity (p = 0.002), shortness of breath (p = 0.02), wheezing (p = 0.029), and ACS (p = 0.014). However, at follow-up, there was no correlation between FEV1 % and any measured index of asthma control. When patients with severe fixed airflow obstruction were excluded from the analysis (n = 16), FEV1 % at follow-up became significantly correlated with night waking (p = 0.02), wheezing (p = 0.05), and ACS (p = 0.036). The improvement in asthma control score at follow-up was significantly and strongly associated (r = 0.51 for total asthma control, p < 0.001) with the improvement in lung function in patients without severe fixed airflow obstruction. Lung function was not associated with any measure of asthma control in patients with severe fixed airflow obstruction. FEV1 % correlates well with asthma symptoms in difficult asthma patients with poor control but not when control improves. This loss of relationship is due to subjects with severe fixed airflow obstruction where good subjective control does not exclude the presence of significant obstruction. How severe fixed airflow obstruction should be prevented, delayed, or managed in asthma requires further research.     

Course of FEV(1) after onset of bronchiolitis obliterans syndrome in lung transplant recipients

RATIONALE: Bronchiolitis obliterans syndrome (BOS), defined by loss of lung function, develops in the majority of lung transplant recipients. However, there is a paucity of information on the subsequent course of lung function in these patients. OBJECTIVES: To characterize the course of FEV(1) over time after development of BOS and to determine the predictors that influence the rate of functional decline of FEV(1). METHODS: FEV(1)% predicted (FEV(1)%pred) trajectories were studied in 111 lung transplant recipients with BOS by multivariate, linear, mixed-effects statistical models. MEASUREMENTS AND MAIN RESULTS: FEV(1)%pred varied over time after BOS onset, with the steepest decline typically seen in the first 6 months (12% decline; p < 0.0001). Bilateral lung transplant recipients had significantly higher FEV(1)%pred at BOS diagnosis (71 vs. 47%; p < 0.0001) and at 24 months after BOS onset (58 vs. 41%; p = 0.0001). Female gender and pretransplant diagnosis of idiopathic pulmonary fibrosis were associated with a steeper decline in FEV(1)%pred in the first 6 months after BOS diagnosis (p = 0.02 and 0.04, respectively). A fall in FEV(1) greater than 20% in the 6 months preceding BOS (termed "rapid onset") was associated with shorter time to BOS onset (p = 0.01), lower FEV(1)%pred at BOS onset (p < 0.0001), steeper decline in the first 6 months (p = 0.03), and lower FEV(1)%pred at 2 years after onset (p = 0.0002). CONCLUSIONS: Rapid onset of BOS, female gender, pretransplant diagnosis of idiopathic pulmonary fibrosis, and single-lung transplantation are associated with worse pulmonary function after BOS onset.     

Risk factors for near-fatal asthma

BACKGROUND: There is a paucity of lung function data in patients, both before and after episodes of near-fatal asthma (NFA), requiring transient endotracheal intubation and mechanical ventilation. METHODS: Lung function was initially measured in 43 asthmatic patients (age range, 16 to 49 years), who were observed and treated in a tertiary referral asthma clinic and were clinically stable at the time of study. Subsequently, clinical and physiologic follow-up studies were obtained over > 5 years. The primary outcomes were to determine (1) the integrity of lung elastic recoil and (2) the severity of expiratory airflow limitation, and (3) to correlate these outcomes with adverse clinical complications. RESULTS: Fourteen of 26 asthmatic patients (54%) [age range, 30 to 49 years] had significantly reduced lung elastic recoil pressures at all lung volumes compared to 3 of 17 asthmatic patients (18%); p = 0.02 [chi(2) test and Fisher exact test] [age range, 16 to 26 years]. In asthmatic patients between the ages of 30 and 49 years, significant loss of lung elastic recoil was noted in 4 of 10 patients with mild reduction in FEV(1) (FEV(1), > 79% predicted), 6 of 12 patients with moderate reduction in FEV(1) (FEV(1), 61 to 79% predicted), and all 4 patients with severe reduction in FEV(1) (FEV(1), < 61% predicted). In asthmatic patients between the ages of 16 and 26 years, significant loss of lung elastic recoil was noted in 0 of 11 patients with mild reduction in FEV(1), 2 of 5 patients with moderate reduction in FEV(1), and 1 of 1 patient with severe reduction in FEV(1). A subgroup of 10 asthmatic patients (7 men) [mean (+/- SD) age, 37 +/- 11 years] were studied when clinically stable, both before and after an episode of NFA in 8 cases and only after an episode of NFA in 2 additional cases. In 1 of 10 cases, the FEV(1) was mildly reduced, in 4 cases it was moderately reduced, and in 5 cases it was severely reduced, both before and after an episode of NFA. The sensitivity was 90%, the specificity was 61%, the positive predictive value was 41%, and the negative predictive value was 95% for NFA with an FEV(1) < or = 79% predicted or FEV(1)/FVC ratio of < 75%. Prior to an episode of NFA, all 8 asthmatic patients had significant loss of lung elastic recoil pressure, and afterward all 10 had significant loss of lung elastic recoil pressure (ie, less than the predicted normal mean minus 1.64 SD at a total lung capacity [TLC] of 100 to 70% predicted). The sensitivity was 100%, the specificity was 79%, the positive predictive value was 59%, and the negative predictive value was 100% for NFA with the loss of lung elastic recoil. The mean TLC measured with a plethysmograph in 10 patients with NFA was 7.2 +/- 1.41 (124 +/- 16% predicted). The sensitivity for TLC of > 115% predicted was 70%, the specificity was 70%, the positive predictive value was 88%, and the negative predictive value was 41% for NFA. CONCLUSION: A persistent reduction in FEV(1) of < or = 79% predicted or an FEV(1)/FVC ratio of < 75%, and, especially, the loss of lung elastic recoil and hyperinflation at TLC are risk factors for NFA. The loss of lung elastic recoil in asthmatic patients was associated with increased age, duration of disease, and progressive expiratory airflow limitation.     

Duration of asthma and lung function in life-long nonsmoking adults.

BACKGROUND: The airways of adult or elderly asthmatics are likely candidates for airway remodeling, resulting in persistent airflow obstruction. This population can provide a good model for cross-sectional evaluation of the effect of asthma duration on airflow. METHODS: We evaluated postbronchodilator airflow and lung volumes at baseline and after a short course of oral prednisone in a group of 42 never-smokers with persistent mild or moderate asthma aged 55 years or older. Patients were grouped as having short duration asthma (SDA, <14 years) or long duration asthma (LDA, > or =14 years) according to the median duration of the disease (14 years) of the sample. RESULTS: There were no significant differences in patient characteristics or asthma severity indices between the groups. After a short course of prednisone, forced expiratory volume in 1 second (FEV1) and the ratio of FEV to forced vital capacity (FVC) were significantly higher for the SDA group. Only 3 patients presented persistent airflow limitation (FEV1/FVC% < 75%). An inverse correlation was demonstrated between duration of asthma and postbronchodilator FEV1 (% predicted) (r = -0.43, P = .01) and FEV1/FVC% (r = -0.50, P = .003). CONCLUSION: Our data show a close relationship between duration of disease and loss of lung function, supporting the concept of asthma as a slow, progressive disease at least among those patients with a mild-to-moderate severity. Permanent airflow obstruction in mild or moderate asthma is unusual, but can occur in a small number suffering from the disease for years.     

Tiotropium and simplified detection of dynamic hyperinflation

STUDY OBJECTIVE: To detect dynamic hyperinflation (DH) by evaluating reduction in inspiratory capacity (IC) during metronome-paced hyperventilation (MPH) in patients with moderate-to-severe COPD, studied before and after treatment with tiotropium. METHODS: IC and FEV(1) were measured before and immediately after MPH at two times resting the respiratory rate for 20 s in 60 COPD patients (28 men; mean age, 66 +/- 10 years [+/- SD]) before and after 30 days of treatment with tiotropium bromide, 18 mug. Patients were encouraged to maintain a constant tidal volume during MPH. RESULTS: At baseline, mean FEV(1) was 1.5 +/- 0.1 L (+/- SE) [57 +/- 1.6% of predicted], mean FVC was 2.6 +/- 0.1L (77 +/- 1.8% of predicted), and mean FEV(1)/FVC was 56 +/- 1%. After 180 mug of aerosolized albuterol sulfate, mean FEV(1) was 1.7 +/- 0.1 L (63 +/- 1.5% of predicted) [p < 0.001] and mean FEV(1)/FVC was 58 +/- 1%. Compared to baseline, after 30 days and 1.5 h after tiotropium there was an increase in IC of 0.18 +/- 0.04L (p < 0.0001); FEV(1) of 0.13 +/- 0.03 L (5.6 +/- 0.8% of predicted; p = 0.0002); FVC of 0.22 +/- 0.05 L (6.5 +/- 1.3% of predicted; p < 0.001); and decrease in end-expiratory lung volume (EELV)/total lung capacity (TLC) of - 3.1 +/- 0.6% (p = 0.0001); a decrease in end-inspiratory lung volume (EILV)/TLC of - 2.9 +/- 1.3% (p = 0.03); and no change in TLC (- 0.06 +/- 0.05 L). Results following MPH-induced DH at baseline and after 30 days of tiotropium were similar, with decreases in IC (- 0.35 +/- 0.03 L; p < 0.001); FEV(1) (- 0.05 +/- 0.04 L; p = 0.2); and FVC (- 0.22 +/- 0.03 L; p < 0.0001); no change in TLC; and increases in EELV/TLC (11.8 +/- 1.0% of predicted; p < 0.0001) and EILV/TLC (4.0 +/- 1.3% of predicted, p < 0.003). CONCLUSION: In patients with moderate-to-severe COPD, tiotropium did not reduce MPH-induced DH and reduction in IC, compared to baseline. However, because tiotropium induced bronchodilation and increased baseline IC, lower operational lung volumes may blunt the effect of MPH-induced DH. The noninvasive simplicity of MPH-induced DH provides a clinically useful screening surrogate to monitor changes in IC following treatment with tiotropium.     

Sputum induction in severe asthma by a standardized protocol: predictors of excessive bronchoconstriction.

Sputum induction is a noninvasive method to evaluate airway inflammation. We investigated whether it can be safely and successfully performed in patients with severe, difficult-to-control asthma, and whether the patients at risk can be identified. Ninety-three severe asthmatics were included, all symptomatic despite inhaled corticosteroids (> or = 1,600 microg/d) and long-acting beta(2)-agonists > 1 yr. Patients with a postbronchodilator FEV(1) < 1 L and < 50% predicted were excluded from participation. Sputum induction was performed according to a strict protocol, using 0.9%, 3.0%, and 4.5% NaCl inhalation. In 74% (CI: 64 to 83%) of patients an adequate sputum sample could be obtained. Twenty-two percent (CI: 14 to 33%) developed excessive bronchoconstriction (decrease in FEV(1) > 15% from baseline) despite the continuing use of long-acting bronchodilators and pretreatment with 400 microg salbutamol. The decrease in FEV(1) was associated with increased use of rescue short-acting beta(2)-agonists in the previous 2 d (r(s) = 0.51, p = 0.002), lower postbronchodilator FEV(1) (r(s) = -0.31, p = 0.004), and lower provocative concentration of histamine causing a 20% reduction in FEV(1) (PC(20)) (r(s) = -0.52, p < 0.001). Recent use of short-acting beta(2)-agonist increased the risk for excessive bronchoconstriction 10.2-fold (CI: 1.2 to 109.8). In conclusion, sputum induction can be safely and successfully performed in patients with severe, difficult-to-control asthma if a standardized protocol is used. However, severe bronchoconstriction may occur despite regular use of long-acting beta(2)-agonist and pretreatment with salbutamol 400 microg. In particular, patients who have used additional short-acting beta(2)-agonists as rescue medication during the days preceding the induction, are at high risk.     

Effects of varying doses of fluticasone propionate on the physiology and bronchial wall immunopathology in mild-to-moderate asthma

OBJECTIVES: Inhaled corticosteroids (ICS) are typically associated with a flat dose-response curve when traditional efficacy values are examined (eg, FEV(1)). The aim of the present study was to investigate if a dose-response relationship exists for lung function and inflammatory cell numbers in bronchial biopsy specimens. METHODS: Bronchial biopsy specimens were obtained from 36 patients randomized to receive 100 micro g, 500 microg, or 2,000 microg/d of fluticasone propionate (FP). Lung physiology and bronchial biopsies were performed at baseline and after 2 weeks of treatment. RESULTS: Improvement in lung function and suppression of airway inflammation were optimal at a dose of 500 microg/d of FP. Significant changes from baseline following treatment were documented in FEV(1) (p = 0.02), forced expiratory flow (p = 0.002), FEV(1)/FVC (p = 0.007), provocative concentration of histamine causing a 20% fall in FEV(1) (PC(20)) [p = 0.02], T-cell numbers (p = 0.0005), activated eosinophils (p = 0.01), and numbers of macrophages (p = 0.01) in the group treated with 500 microg/d of FP. Comparison between groups administered different doses of FP failed to demonstrate a dose-response relationship for change from baseline in PC(20) (p = 0.43), any of the lung function parameters, T-cell numbers (p = 0.64), activated T cells (p = 0.46), eosinophils (p = 0.53), activated eosinophils (p = 0.48), or macrophage numbers (p = 0.68). CONCLUSION: The apparent lack of a dose-response for ICS treatment in patients with asthma further validates the preferential use of add-on therapy over increasing the dose of ICS.     

A randomized study comparing ciclesonide and fluticasone propionate in patients with moderate persistent asthma

OBJECTIVE: To compare the effects of once-daily ciclesonide and twice-daily fluticasone propionate in patients with moderate persistent asthma. METHODS: Patients aged 12-75 years with moderate bronchial asthma entered a 1-4 week run-in period. For inclusion into the 12-week, randomized, open-label treatment period, patients had to have a forced expiratory volume in 1s (FEV1) of either 60-80% of predicted or 80% of predicted and a defined use of rescue medication and asthma symptoms, depending on previous treatment. Patients received ciclesonide 320 microg once daily (ex-actuator) or fluticasone propionate 200 microg twice daily. Primary efficacy endpoint was change from baseline in FEV1. RESULTS: In total, 474 patients were randomized. FEV1 increased significantly from baseline with ciclesonide and fluticasone propionate in the intention-to-treat (ITT) and per-protocol (PP) analyses (all p < 0.0001). Treatment difference was -31 mL (95% confidence interval [CI]: -121, 59) in the PP analysis, demonstrating non-inferiority of ciclesonide. Similar findings were seen for other measures of lung function. In the ITT population, asthma symptom scores and rescue medication use decreased with both treatments (all p < 0.0001). Improvement in health-related quality of life (HRQoL) from baseline was significantly greater with ciclesonide than fluticasone (p = 0.005; one-sided). There were no cases of oral candidiasis in patients receiving ciclesonide and nine cases (3.8%) in those receiving fluticasone propionate (p = 0.002; one-sided). CONCLUSIONS: Treatment with once-daily ciclesonide and twice-daily fluticasone propionate resulted in similar improvements in lung function in patients with moderate persistent asthma. Ciclesonide showed significant improvements in oral candidiasis and HRQoL over fluticasone.     

Association between neutrophilic airway inflammation and airflow limitation in adults with asthma

BACKGROUND: There is debate about the mechanisms of persistent airflow limitation in patients with asthma. Chronic inflammation is assumed to be important, although there is limited and contradictory information about the relationship between airway inflammation and postbronchodilator FEV1. METHODS: We have assessed the cross-sectional relationship between prebronchodilator and postbronchodilator FEV1 and measures of airway inflammation after allowing for the effects of potential confounding factors. Multivariate analysis was performed on data collected from 1,197 consecutive patients with asthma seen at the respiratory outpatient clinic at Glenfield Hospital between 1997 and 2004. Relationships between induced sputum total neutrophil and differential eosinophil cell counts, and prebronchodilator and postbronchodilator lung function were examined. RESULTS: Sputum total neutrophil but not differential eosinophil count was associated with lower postbronchodilator FEV1. Both differential eosinophil and total neutrophil count were associated with lower prebronchodilator FEV1. These effects were independent after adjustment for age, smoking, ethnicity, asthma duration, and inhaled corticosteroid use. A 10-fold increase in neutrophil count was associated with a 92 mL reduction (95% confidence interval, 29 to 158; p = 0.007) in postbronchodilator FEV1. CONCLUSIONS: In this large heterogeneous population of adults with asthma, we have shown that prebronchodilator FEV1 is associated with neutrophilic and eosinophilic airway inflammation, whereas sputum total neutrophil counts alone are associated with postbronchodilator FEV1. This supports the hypothesis that neutrophilic airway inflammation has a role in the progression of persistent airflow limitation in asthma and raises the possibility that this progression and the development of COPD share a common mechanism.     

Health status deterioration in patients with chronic obstructive pulmonary disease

This study examined health status decline in patients with chronic obstructive pulmonary disease (COPD). Data are from the Inhaled Steroids in Obstructive Lung Disease (ISOLDE) trial. After an 8-wk run-in, 751 patients (566 male), mean age 64 yr, were randomized to receive fluticasone propionate (FP) 500 microg twice daily (376 patients) or placebo (375 patients). Mean baseline postbronchodilator FEV1 was 50 +/- 15% predicted. Patients completed the St George's Respiratory Questionnaire (SGRQ) and the Short-Form 36 (SF-36) at baseline and every 6 mo for 3 yr. FEV1 and smoking status were assessed at baseline and at 3-mo intervals. A total of 387 (212 FP) patients completed the trial. All SGRQ components (p = 0.03 to 0.004) and Physical Function, Mental Health, Energy/ Vitality, and Physical Role Limitation scales of the SF-36 (p = 0.05 to 0.005) deteriorated faster in the placebo group. FEV1 and SGRQ scores correlated at baseline values (r = -0.25, p < 0.0001), as did change in FEV1 and change in SGRQ (Delta r = -0.24, p < 0.0001). At baseline values smokers had worse SGRQ Total, Symptoms, and Impacts scores than ex-smokers. This difference was maintained throughout the study. Smoking status did not influence the rate of decline in health status. The SGRQ Total scores of FP-treated patients took 59% longer than placebo to deteriorate by a clinically significant amount. We conclude that health status decline in moderate to severe COPD can be reduced by high-dose fluticasone.     

Genomewide screen for pulmonary function in 200 families ascertained for asthma

Changes in pulmonary function are important in determining asthma outcome. Genetic factors may influence airway obstruction in asthma. We performed a genomewide screen in 200 families of probands objectively diagnosed with asthma in the 1960s to identify chromosomal regions related to changes in pre- and postbronchodilator lung function (FEV1, VC, and FEV1%VC) and assess influences of early-life smoke exposure. Smoking (pack-years), age, sex, and height were covariates in variance component analyses. Significant evidence for linkage of pre- and postbronchodilator FEV1%VC was obtained for chromosome 2q32 (LOD,4.9, increasing to 6.03 with additional fine-mapping markers, and 3.2, respectively). Linkage existed for chromosome 5q for pre- and postbronchodilator VC (likelihood of disease [LOD], 1.8 and 2.6, respectively). Results for pre- and postbronchodilator FEV1 were less significant (LOD, 1.5 and 1.6, chromosomes 11p and 10q, respectively). Results were not affected by passive smoke exposure. There is significant evidence for linkage of FEV1%VC to chromosome 2q32 in families of probands with asthma, 35 cM proximal from linkage previously observed in families of probands with early-onset chronic obstructive pulmonary disease. Thus, there may be multiple genes on chromosome 2q that are important in determining presence and degree of airflow limitation in families ascertained for obstructive airway disease.     

Pulmonary hypertension and cardiac function in adult cystic fibrosis: role of hypoxemia.

STUDY OBJECTIVES: To determine (1) the prevalence of pulmonary hypertension and cardiac dysfunction in adult cystic fibrosis (CF) patients with severe lung disease, (2) the relationship between these cardiovascular abnormalities and hypoxemia, and (3) the impact of subclinical pulmonary hypertension on survival. DESIGN: Single-blind, cross-sectional study. SETTING: Ambulatory clinic of the Adult CF program at a tertiary-level hospital. PATIENTS: Clinically stable patients with severe lung disease (FEV1 < 40% of predicted normal value) who were not receiving supplemental oxygen. A second cohort of patients in stable condition with less severe lung disease (FEV1 40 to 65% predicted) was also recruited to enable multivariate analysis for the determinants of pulmonary hypertension. MEASUREMENTS AND RESULTS: Eighteen patients with severe lung disease (FEV1 28 +/- 7% of predicted normal value) were initially studied. Each patient had overnight polysomnography, pulmonary function tests, and Doppler echocardiography. Arterial oxygen saturation (SaO2) was reduced during wakefulness (87.1 +/- 6.1%) and fell during sleep (84.0 +/- 6.6%) while transcutaneous PCO2 was normal during wakefulness (41.1 +/- 6.9 mm Hg) and increased during sleep (46.6 +/- 4.7 mm Hg). Left ventricular size, systolic function, and diastolic function were normal except in one patient who had had a previous silent myocardial infarction due to coronary artery disease. Qualitative assessment of right ventricular function was normal in all patients. Pulmonary artery systolic pressure (PASP) was increased (> 35 mm Hg) in seven patients without clinical evidence of cor pulmonale. Regression analysis was performed by combining these data with data from an additional 15 CF patients with moderately severe lung disease (FEV1 56.3 +/- 8.9% predicted normal) who were recruited to a modified study protocol that included overnight oximetry, pulmonary function tests, and Doppler echocardiography. None of these patients had evidence of hypoxemia and only three had mild elevation of PASP (36, 37, and 39 mm Hg). Linear regression analysis revealed that PASP was significantly correlated with FEV1 (r = -0.44; p = 0.013), and SaO2 during wakefulness (r =-0.60; p = 0.0003), during sleep (r = -0.56; p = 0.0008), and after 6 min of exercise (r = -0.75; p < 0.0001). Multivariate analysis revealed that awake SaO2 was a significantly better predictor of PASP than FEV1 (p = 0.0104). Clinical follow-up of the original cohort for up to 5 years revealed that mortality was significantly higher in those with pulmonary hypertension than those without pulmonary hypertension (p = 0.0129). CONCLUSIONS: In adult CF patients with severe stable lung disease, left and right ventricular function is well maintained in the absence of significant coronary artery disease; pulmonary hypertension develops in a significant proportion of patients and is strongly correlated with oxygen status, independent of lung function; and subclinical pulmonary hypertension is associated with an increased mortality.     

Interferon therapy induces the improvement of lung function by inhaled corticosteroid therapy in asthmatic patients with chronic hepatitis C virus infection: a preliminary study

STUDY OBJECTIVES: Several reports have suggested that subsets of asthmatic patients with chronic viral infection fail to respond to corticosteroid therapy. Therefore, this study was designed to determine that asthmatic patients with chronic hepatitis C virus (HCV) infection fail to improve lung function by inhaled corticosteroid therapy, and that interferon (IFN) therapy against HCV is effective for such patients. DESIGN: Prospective observational study. SETTING: University hospital. PATIENTS: Forty asthmatic patients with chronic HCV infection. INTERVENTIONS: After a 4-week run-in period, all asthmatic patients received therapy with inhaled beclomethasone dipropionate (BDP), 400 micro g twice daily for 6 weeks. After the first study, all asthmatic patients continued to receive inhaled BDP, and 30 HCV-positive asthmatic patients received IFN-alpha therapy for 6 months. MEASUREMENTS AND RESULTS: Prebronchodilator and postbronchodilator FEV(1) values were examined after a 4-week run-in period, after 6 weeks of BDP therapy, and at 1 year from the end of IFN therapy. After a 4-week run-in period as well as after 6 weeks of BDP therapy, there were no significant differences in either prebronchodilator or postbronchodilator FEV(1) values among the three groups. However, 1 year after the end of IFN therapy, the mean prebronchodilator and postbronchodilator FEV(1) values were significantly higher in the IFN responder group (n = 11) [prebronchodilator FEV(1), 1.93 L (SD, 0.13 L); postbronchodilator FEV(1), 2.28 L (SD, 0.15 L)] than in the IFN nontreatment group (n = 10) [prebronchodilator FEV(1), 1.78 L (SD, 0.10 L); p = 0.01; postbronchodilator FEV(1), 2.07 L (0.13 L); p = 0.005] or the IFN nonresponder groups (n = 19) [prebronchodilator FEV(1), 1.79 L (SD, 0.15 L); p = 0.006; postbronchodilator FEV(1), 2.07 L (SD, 0.18 L); p = 0.002]. Moreover, prebronchodilator and postbronchodilator FEV(1) values were significantly higher only in the IFN responder group at 1 year after the end of IFN therapy than after the 4-week run-in period (prebronchodilator FEV(1), p = 0.028; postbronchodilator FEV(1); p = 0.002) or after 6 weeks of BDP therapy (p = 0.016 and p = 0.004, respectively). CONCLUSIONS: Our findings suggest that chronic HCV infection in asthmatic patients is associated with impaired responses to inhaled BDP therapy and that intervention with IFN reverses such responses only in the IFN responder group.     

Dyspnea perception and reversibility of methacholine-induced unlimited airway narrowing in asthmatics.

The hypothesis was that asthmatics might experience impaired perception of dyspnea and salbutamol-induced reversibility during unlimited airway narrowing. A total of 38 asthmatics (18 to 59 years of age) were examined. All patients underwent the methacholine challenge test. According to the dose-response curve to methacholine, they were categorized as having either unlimited airway narrowing (UAN group) (n = 20) or response plateau (RP group) (n = 18). Reversibility of methacholine-induced bronchoconstriction was measured 20 minutes after the inhalation of 400 microg of salbutamol to compare postbronchodilator FEV1 with baseline FEV1. Dyspnea perception was evaluated using the Borg Scale to calculate a perception score at a 20% decrease in FEV1 (PS20) and the slope alpha of the regression line between the changes in Borg scores and the reduction in FEV1 as percentage of the baseline value. Subjects in the UAN group exhibited significantly lower PS20 compared with the RP group (1.45+/- 0.23 vs. 2.84 +/- 0.35, p = 0.002); the mean of the slope values was higher in the RP group than it was in the UAN group (0.150 +/- 0.015 vs. 0.095 +/- 0.006, p = 0.003). Salbutamol-induced reversibility was significantly lower in the UAN group (81 +/- 1.4 % of baseline FEV1) compared with patients from the RP group (91 +/- 1.1% of baseline FEV1; p < 0.001). In conclusion, asthmatics during methacholine-induced unlimited airway narrowing exhibit diminished perception of dyspnea and lower bronchial reversibility to the baseline 20 minutes after inhalation of salbutamol. This suggests that more careful monitoring of the lung function for timely recognition of asthma deteriorations and adequate bronchodilatory therapy during severe acute attacks should be recommended for such patients.     

Pulmonary function characteristics in patients with different patterns of methacholine airway hyperresponsiveness

STUDY OBJECTIVES: The American Thoracic Society guidelines for methacholine-induced airway hyperresponsiveness include a > or = 20% reduction in FEV(1) or a > or = 40% reduction in specific airway conductance (sGaw). The objectives of the current study are to assess the concordance between these two criteria and to characterize the pulmonary function and respiratory symptoms of patients with different patterns of methacholine hyperresponsiveness. STUDY DESIGN: A prospective study of 248 consecutive patients referred for methacholine bronchoprovocation testing. RESULTS: Positive methacholine hyperresponsiveness was noted in 179 patients; 139 patients (78%) had a > or = 20% reduction in FEV(1), whereas 40 patients (22%) had a > or = 40% reduction in sGaw alone without a significant change in FEV(1). The former group had the following: (1) higher baseline lung volumes, (2) lower baseline values of FEV(1) and sGaw, (3) forced expiratory flow between 25% and 75% of vital capacity (FEF(25-75))/FVC ratios compared to patients with a reduction in sGaw alone (0.72 +/- 0.26 vs 0.97 +/- 0.28, mean +/- SD; p < 0.0001), and (4) more frequent presence of wheezing and chest tightness (p < 0.05). CONCLUSIONS: First, a substantial number of patients have a reduction in SGaw alone in response to methacholine, and secondly, this response is seen in patients with a higher FEF(25-75)/FVC ratio. Since the FEF(25-75)/FVC ratio is thought to be an index of airway size relative to lung size, we speculate that the larger intrinsic airway size relative to lung size may explain the differences in baseline parameters and patterns of methacholine hyperresponsiveness.     

Stair climbing test predicts cardiopulmonary complications after lung resection

STUDY OBJECTIVE: To evaluate the capability of the stair climbing test to predict cardiopulmonary complications after lung resection for lung cancer. DESIGN: A prospective cohort of candidates for lung resection. Spirometric assessment and the stair climbing test were performed the day before operation. Univariate and multivariate analyses were performed to identify predictors of postoperative complications. SETTING: Tertiary referral center. PATIENTS: A consecutive series of 160 candidates for lung resection with lung carcinoma from January 2000 through March 2001. RESULTS: At univariate analysis, the patients with complications were significantly older (p = 0.02), had a significantly lower FEV(1) percentage (p = 0.007) and predicted postoperative FEV(1) percentage (p = 0.01), had a greater incidence of a concomitant cardiac disease (p = 0.02), climbed a lower altitude at the stair climbing test (p < 0.0001), and had a lower calculated maximum oxygen consumption (O(2)max) [p = 0.03] and predicted postoperative O(2)max (p = 0.006) compared to the patients without complications. At multivariate analysis, the altitude reached at the stair climbing test remained the only significant independent predictor of complications. CONCLUSIONS: The stair climbing test is a safe and economical exercise test, and it was the best predictor of cardiopulmonary complications after lung resection.     

Effects of montelukast treatment and withdrawal on fractional exhaled nitric oxide and lung function in children with asthma

BACKGROUND: Leukotriene receptor antagonists (LTRAs) reduce fractional exhaled nitric oxide (Feno) concentrations in children with asthma, but the effect of LTRA withdrawal on Feno and lung function is unknown. We aimed to study the effect of treatment and withdrawal of montelukast, a LTRA, on airway inflammation as reflected by Feno and lung function in children with asthma. METHODS: A double-blind, randomized, placebo controlled, parallel group study was undertaken in 14 atopic children with mild persistent asthma who were treated with oral montelukast (5 mg/d for 4 weeks) and 12 atopic children with mild persistent asthma who received matching placebo. A follow-up visit was performed 2 weeks after montelukast or placebo withdrawal. RESULTS: Montelukast reduced Feno concentrations by 17% (p = 0.067), an effect that was more pronounced (35%) [p = 0.0029] when children with seasonal atopy who were exposed to relevant allergens during the treatment phase were excluded from analysis (n = 3). Compared to those at the end of treatment, Feno concentrations were increased 2 weeks after montelukast withdrawal (p = 0.023) concomitant with a reduction in absolute FEV(1) values (p = 0.011), FEV(1) percentage of predicted values (p = 0.006), FEV(1)/FVC ratio (p = 0.002), and forced expiratory flow at 25% to 75% of FVC values (p = 0.021). These changes were not observed in the placebo group. CONCLUSIONS: LTRAs reduce Feno concentrations in children with asthma, and withdrawal can result in increased Feno values and worsening of lung function in children with asthma.