Recombinant human DNase nebulisation in children with cystic fibrosis: before bedtime or after waking up?

The present study focused on patients with cystic fibrosis (CF), who were on maintenance therapy with recombinant human deoxyribonuclease (rhDNase), with the aim of comparing efficacy and possible side effects of nebulisation of rhDNase when taken before bedtime with efficacy and side effects when taken after waking up. A randomised, double-blind, double-dummy, crossover study group was used. The inclusion criteria were as follows: 1) CF, 2) stable clinical condition and 3) rhDNase maintenance therapy. Patients in group I inhaled rhDNase before bedtime and a placebo after waking up in weeks 1-2. The protocol was reversed during weeks 3-4. Group II patients performed the reverse of this sequence. Patients continued with their daily routine sputum expectoration. The primary end-point was classified as the maximal instantaneous forced flow when 25% of the forced vital capacity remained to be exhaled (MEF(25%)). Pulmonary functions tests were performed on days 0, 7, 14, 21 and 28. At 1, 2, 3 and 4 weeks arterial oxygen saturation and cough frequency were measured during the night. A total of 24 patients completed the study. The mean (range) age of the patients was 13 (6-19) yrs. MEF(25%), taken to be the primary end-point, did not show a significant difference between nebulisation of rhDNase before bedtime compared with when taken after waking up. Nocturnal cough, oxygen saturation, and other secondary end-points were not significantly different between the two study periods. In conclusion, the present study found that it is equally effective and safe to nebulise recombinant human deoxyribonuclease before bedtime compared with when performed after waking up in children with cystic fibrosis, who are on maintenance treatment with recombinant human deoxyribonuclease.     

Effects of recombinant human DNase and hypertonic saline on airway inflammation in children with cystic fibrosis

Recombinant human DNase (rhDNase) is an established treatment in cystic fibrosis (CF), but it may liberate cationic mediators bound to DNA in the airways. An alternative mucolytic therapy is hypertonic saline (HS); however, HS may potentiate neutrophilic inflammation. We compared the effect of rhDNase and HS on cationic proinflammatory mediators in CF sputum. In a randomized, crossover trial, 48 children with CF were allocated consecutively to 12 weeks of once-daily 2.5 mg rhDNase, alternate-day 2.5 mg rhDNase, and twice-daily 7% HS. Sputum levels of total interleukin-8 (IL-8), free IL-8, myeloperoxidase, eosinophil cationic protein, and neutrophil elastase (NE) activity were measured before and after each treatment. The change in mediator levels from baseline with daily rhDNase and HS was not significant; however, with alternate-day rhDNase, there was an increase in free IL-8. When changes in mediator levels with daily rhDNase were compared with alternate-day rhDNase and HS, no significant differences were detected. Only changes in NE activity were associated with changes in lung function. In summary, we were unable to show that rhDNase or HS promote airway inflammation in CF.     

Predicting response to rhDNase and hypertonic saline in children with cystic fibrosis

Daily recombinant human deoxyribonuclease (rhDNase) is an established but expensive treatment in cystic fibrosis (CF). Alternate-day rhDNase and hypertonic saline (HS) represent potential cheaper alternative therapies. However, not all patients improve on treatment. To assess response, many CF centers have developed formal n-of-1 trials of treatment to find out who benefits. Response to daily rhDNase at 3 months has been shown to be a good predictor of response at 1 year. There are no data correlating individual response at a shorter time period with 3-month response. We assessed whether individual responses to daily rhDNase, alternate-day rhDNase, and HS could be predicted from lung function response at 6 weeks, thus shortening the n-of-1 trial, or from baseline patient characteristics, therefore avoiding the need for an n-of-1 trial. In a randomized crossover trial, 48 CF children were allocated consecutively to 12 weeks of once-daily 2.5-mg rhDNase, alternate-day 2.5-mg rhDNase, and twice-daily 5 ml of 7% HS. Forced expiratory volume in 1 sec (FEV1) and forced vital capacity (FVC) were measured at baseline and then at 6 and 12 weeks into each treatment period. Lung function response to the drugs at 6 weeks was highly predictive of response at 3 months. There was some evidence that response to HS was worse in patients with lower baseline lung function. However, there was no association between response to alternate-day or daily rhDNase and baseline characteristics. In conclusion, response to rhDNase and HS at 6 weeks was highly predictive of response at 3 months. For daily and alternate-day rhDNase, at least, the drug needs to be administered for at most 6 weeks initially to assess long-term response to treatment. Response to treatment could not be reliably predicted from baseline characteristics.     

Improved activity of an actin-resistant DNase I variant on the cystic fibrosis airway secretions

In cystic fibrosis (CF), actin and DNA originating from inflammatory cells contribute to the thickness of airway secretions. Actin can bind to DNA-rich fibers and potently inhibit the enzymatic activity of rhDNase. The in vitro effects of the actin-resistant rhDNase variant (A114R) were analyzed and compared with those of the wild-type rhDNase. Frozen and thawed CF airway secretions were incubated for 30 min with different concentrations (0.1, 0.5, 1, 5, or 10 microg/ml) of either actin-resistant rhDNase or wild-type rhDNase. We observed that both the wild-type and the actin-resistant rhDNase significantly decreased (p < 0.05 and p < 0.001, respectively) the airway secretion viscosity. The decrease in airway secretion viscosity was significant even at low concentrations (0.1 microg/ml) of the actin-resistant variant. Incubation with the actin-resistant variant resulted in a significant decrease (p < 0.02) of the airway secretion contact angle and cough transport. A significantly higher (p < 0.01) increase in contact angle and cough transport of airway secretions was observed at 10 microg/ml with the actin-resistant variant as compared with the wild-type rhDNase. The present study had demonstrated that the actin-resistant rhDNase variant (A114R) has an enhanced capacity to improve the physical properties and cough transport of airway secretions from patients with cystic fibrosis.     

Effect of treatment with dornase alpha on airway inflammation in patients with cystic fibrosis

Recombinant human deoxyribonuclease (rhDNase) has been shown to improve lung function and reduce the number of pulmonary exacerbations in patients with cystic fibrosis (CF), but its long-term effect on airway inflammation remains unknown. In this study, we used bronchoalveolar lavage (BAL) to investigate the long-term effect of rhDNase on inflammation in patients with CF having mild lung disease. A total of 105 patients with CF (> or =5 years of age) having normal lung function were randomized to receive rhDNase (2.5 mg/day) or no rhDNase. Patients with a normal percentage of neutrophils in BAL fluid at baseline were not randomized and served as the control group. The percentage of neutrophils in the pooled BAL sample was similar in both randomized groups at baseline. A significant increase in neutrophils was observed over the 3-year study period in both untreated patients and control subjects, whereas neutrophils remained unchanged in patients treated with rhDNase. Elastase activities and interleukin-8 concentrations also increased in untreated patients and remained stable in patients on rhDNase. We conclude that in patients with CF, an increase in neutrophilic airway inflammation is found that is positively influenced by rhDNase treatment.     

Airway inflammation after treatment with aerosolized deoxyribonuclease in cystic fibrosis

Recombinant human deoxyribonuclease (rhDNase) has been shown to reduce sputum viscoelasticity and to improve lung function in patients with cystic fibrosis (CF). The aim of this study was to determine whether airway inflammation would decrease after administration of rhDNase. Twenty patients with CF and chronic suppurative lung disease inhaled 2.5 mg of rhDNase daily for 1 month. Before and after the 1-month trial, lung function was measured and sputum was obtained, either after spontaneous expectoration or after sputum induction with hypertonic saline. Sputum total cell and differential counts were measured using techniques previously described. The mean age of the patients was 16.8 years (range, 6.7–27.5). After 1 month of rhDNase, mean FEV₁ increased from a baseline of 62.3% predicted to 70.8% (P = 0.02, paired t test); and FVC increased from 74.4% to 83.9% predicted (P = 0.007). No significant differences were found in sputum cytology before or after rhDNase (median total cell counts 16.0 × 10⁶/ml vs. 19.3 × 10⁶/ml, P = 0.68). Thirteen patients had a 10% or greater increase in FEV₁ after rhDNase (responders). Initial lung function was less in responders than in nonresponders (53.5% vs. 78.6%, P = 0.007). There was no significant change in total cell count and neutrophil count after rhDNase in either responders or nonresponders. We conclude that airway inflammation, as measured by total cell counts in sputum, was a prominent feature in cystic fibrosis, and neutrophils were the dominant inflammatory cells. Although the administration of rhDNase resulted in significant improvements in FEV₁, there was no evidence of accompanying changes in airway inflammation. Pediatr Pulmonol. 1998;26:97–100. © 1998 Wiley-Liss, Inc.     

Dornase alfa reduces air trapping in children with mild cystic fibrosis lung disease: a quantitative analysis

PURPOSES: To evaluate quantitative air trapping measurements in children with mild cystic fibrosis (CF) lung disease during a 1-year, double-blind, placebo-controlled, recombinant human deoxyribonuclease (rhDNase) [dornase alfa] intervention trial and compare results from quantitative air trapping with those from spirometry or visually scored high-resolution CT (HRCT) scans of the chest. MATERIALS AND METHODS: Twenty-five children with CF randomized to either daily rhDNase or placebo aerosol were evaluated at baseline, and at 3 months and 12 months by spirometer-triggered HRCT and spirometry. Outcome variables were percentage of predicted FVC, FEV1, and forced expiratory flow, midexpiratory phase (FEF(25-75%)); total and subcomponent visual HRCT scores; and quantitative air trapping measurements derived from chest HRCT images. RESULTS: At baseline, there were no statistical differences between groups in any of the variables used as an outcome. After 3 months of treatment, both groups had improvements in percentage of predicted FEV1 and FEF(25-75%), and total HRCT visual scores. In contrast, the rhDNase group had a 13% decrease in quantitative air trapping from baseline (severe air trapping [A3]), compared to an increase of 48% in the placebo group (p = 0.023). After 12 months, both groups had declines in percentage of predicted FVC and FEV1, but the rhDNase group retained improvements in percentage of predicted FEF(25-75%) and quantitative air trapping. The mucus plugging and total HRCT visual scores were also improved in the rhDNase group after 12 months of treatment, with and without significant differences between groups (p = 0.026 and p = 0.676). Quantitative air trapping (A3) remained improved in the rhDNase group (- 15.4%) and worsened in the placebo group (+61.3%) with nearly significant differences noted between groups (p = 0.053) after 12 months of treatment. CONCLUSIONS: Quantitative air trapping is a more consistent sensitive outcome measure than either spirometry or total HRCT scores, and can discriminate differences in treatment effects in children with minimal CF lung disease.     

Computed tomography reflects lower airway inflammation and tracks changes in early cystic fibrosis

RATIONALE: Detecting and tracking early cystic fibrosis (CF) lung disease are difficult due to lack of sensitive markers of airway dysfunction. OBJECTIVES: The goals were to detect regional distribution of airway disease through high-resolution computed tomography, correlate abnormalities to lower airway inflammation/infection, and compare computed tomography findings before and after intravenous antibiotic therapy in children with CF younger than 4 years experiencing a pulmonary exacerbation. METHODS: High-resolution computed tomography was performed in 17 children scheduled for bronchoscopy. The radiologist identified the lobes with the "greatest" and "least" disease based on computed tomography, and bronchoalveolar lavage was performed in these areas. In 13 subjects, imaging was repeated after antibiotic completion. Modified Brody scores were assigned by two radiologists. MEASUREMENTS AND MAIN RESULTS: The lobe with greatest disease was predominantly localized to the right and had higher modified Brody scores, indicating more severe abnormalities (p < 0.01), compared with the lobe with least disease. The total modified Brody score (p < 0.01), hyperinflation subscore (p < 0.01), and bronchial dilatation/bronchiectasis subscore (p < 0.01) improved after antibiotics and intensified airway clearance. Interleukin-8 levels (p < 0.01) and % neutrophils (p = 0.04) were increased in the lobe with greatest disease compared with the lobe with least disease. CONCLUSIONS: These results indicate that, in young children with CF experiencing a pulmonary exacerbation, computed tomography detects regional differences in airway inflammation, may be a sensitive outcome to evaluate therapeutic interventions, and identifies early lung disease as being more prominent on the right.     

Firefighting acutely increases airway responsiveness

The acute effects of the products of combustion and pyrolysis on airway responsiveness among firefighters are poorly documented. To study this relationship, spirometry and methacholine challenge testing (MCT) were performed on 18 active Seattle firefighters before and 5 to 24 h after firefighting. Body plethysmography was used to measure changes in specific airway conductance (SGaw), and results of MCT were analyzed using PD35-SGaw, the cumulative dose causing a 35% decrease in SGaw. Subjects who did not react by the end of the protocol were assigned a value of 640 inhalational units, the largest cumulative dose. Fire exposure was defined as the total time (hours) spent without a self-contained breathing apparatus at the firesite and was categorized as mild (less than 1 h, n = 7), moderate (1 to 2 h, n = 5), or severe (greater than 2 h, n = 6). Mean age of the 18 firefighters was 36.7 +/- 6.7 yr (range, 25 to 51), with a mean of 9.1 +/- 7.9 active years in the trade (range, zero to 22). None was known to be asthmatic. After firefighting, FEV1 % predicted (%pred) and FEF25-75 %pred significantly decreased by means of 3.4 +/- 1.1% and 5.6 +/- 2.6%, respectively. The mean decline in PD35-SGaw after firefighting was 184.5 +/- 53.2 units (p = 0.003). This observed decline in PD35-SGaw could not be explained by decrements in prechallenge SGaw, FEV1, or FVC.(ABSTRACT TRUNCATED AT 250 WORDS)     

Benefits of an education programme on the self-management of aerosol and airway clearance treatments for children with cystic fibrosis

Adherence to recommended aerosol medicines and airway clearance techniques (ACT) for children with cystic fibrosis (CF) requires self-management skills. A multi-centre, randomized, controlled trial was conducted to investigate the effectiveness of a self-management education programme called 'Airways' for six- to 11-year old children with CF and their caregivers. Assessments were conducted immediately before and after the intervention period, and six and 12 months after the post-intervention assessment. The pen and paper education programme was completed by the child and caregiver together at home. Participants in the intervention and control groups had similar baseline characteristics. A per-protocol analysis was conducted and for variables that changed significantly, an additional intention-to-treat analysis was performed that included data from participants in the intervention group who withdrew from the study during the intervention period. The intervention group increased the percentage of prescribed aerosols taken (P < 0.001) and this was maintained at 12-month follow-up (P < 0.001). There was no change in the percentage of prescribed ACT performed, although when the child was unwell, caregivers in the intervention group increased the frequency and/or duration of ACT (P = 0.028) in the per-protocol analysis but not in the intention-to-treat analysis. Children in the intervention group increased their knowledge of ACT (P < 0.001) which was maintained at 12-month follow-up (P < 0.001) and felt more positively about their chest treatment regimens immediately following the intervention (P = 0.017) but not at 12-month follow-up. There were no significant changes in the control group for these variables over time. No significant changes occurred in the caregivers' reports of self-management behaviours and self-efficacy in either group. The positive results suggest that 'Airways' is a valuable educational tool for primary school-aged children with CF and their caregiver.     

Effect of DNase on exercise capacity in cystic fibrosis

DNase can reduce viscosity and facilitate expectoration of airway secretions in cystic fibrosis (CF) lung disease. We evaluated its effect on exercise performance in relation to resting pulmonary function. Fifteen sputum-producing CF patients (aged 9-28 years; FEV1 22-83% predicted) performed spirometry, body plethysmography, nitrogen washout, and incremental cardiopulmonary exercise testing before and after 8 weeks of first-time treatment with daily inhaled rhDNase. Most subjects reported increased amounts and fluidity of sputum. The effect on objective parameters was heterogeneous, without statistical significance. Groupwise, FEV1 increased by 6% without correlation to baseline values; individual patients gained up to 40%. Indices of hyperinflation and air trapping were slightly raised. Maximal workload and oxygen uptake (V'O2) increased by up to 20% in a number of patients. The treatment effect on V'O2 was neither related to baseline levels of pulmonary function and exercise capacity nor to the change in FEV1. Ventilatory equivalents for oxygen and carbon dioxide during exercise were slightly but insignificantly lower after DNase treatment; minimal O2 saturation was unaffected. We conclude that improvement of exercise performance with DNase is restricted to a subgroup of CF patients and may not be predicted or identified by spirometry and subject report alone.     

An isoflow-volume technique for assessing airway dynamics in children and adults

BACKGROUND: We propose a new approach to the measurement of small airway function as an alternative to recordings of maximal expiratory flow-volume (MEFV) curves. OBJECTIVES: A newly developed technique to record isoflow-volume (IFV) curves to be tested against maximal respiratory flow curves. METHODS: An isoflow whistle (IFW; Iflopen) measures the length of a constant expiration after full inspiration. The note of the whistle enables a subject to generate an even expiration, and the isoflow maintenance times at 1 l x s(-1) (IFMT1) and 2 l x s(-1) (IFMT2) are recorded. The accuracy and reproducibility of the IFV technique were evaluated in 17 healthy adults (age 17-55 years) and in 14 asthmatic children (age 6-14 years). Comparisons with standard lung function parameters, such as forced expiratory volume in 1 s (FEV1), maximal expiratory flow at 50% (MEF50) and 25% (MEF25) vital capacity and peak expiratory flow (PEF), obtained with a Wright Peakflow Meter were undertaken in 102 healthy (aged 8-14 years) and 101 asthmatic children (aged 6-17 years). A bronchial challenge test was performed in 13 asthmatic children. RESULTS: The expired volume measured by the IFW showed an acceptable agreement with that of a pneumotachograph (mean error of 4.32% for IFMT1 and 5.93% for IFMT2). In healthy and in asthmatic children, the correlations between FEV1 and IFMT1 or IFMT2 (r = 0.92 and 0.94, respectively) were found to be greater than that between FEV1 and PEF (r = 0.68). During bronchial challenge tests in 13 asthmatic children, the FEV1 decreased to 69% of baseline and IFMT1 to 58% of baseline. CONCLUSIONS: The IFV technique accurately measured airway obstruction and closely followed changes in standard parameters of the MEFV curve.     

Effects of administration of aerosolized recombinant human deoxyribonuclease on resting energy expenditure in patients with cystic fibrosis

By improving pulmonary function in patients with cystic fibrosis (CF), recombinant human deoxyribonuclease (rhDNase) may affect resting energy expenditure (REE). To examine this hypothesis, we measured REE by indirect calorimetry in seven patients with CF before (day 0) and 2 weeks after (day 15) administration of aerosolized rhDNase. Baseline REE was higher in all patients than predicted for age, sex, and weight (mean ± SEM 128±4.9%; range, 116–147%). After 2 weeks of aerosolized rhDNase, mean forced vital capacity (FVC) (in % of predicted values) improved significantly from 54.1 ± 2.2 to 66.3±4.2% (mean improvement, 12.3%; 95% Cl, 2.8,21; P < 0.05) and REE decreased by 11.0% (95% Cl 3.2, 17.5; P < 0.05). In addition, the larger the improvement in FVC in response to rhDNase the greater the decrease in energy expenditure (r – 0.88). The REE decreased in all patients who had an increase in FVC and remained unchanged in two patients who had no change in FVC. We conclude that patients with CF whose lung function improve in response to aerosolized rhDNase have an acute and proportionate reduction in their resting energy expenditure. Pediatr Pulmonol. 1994;18:150–154. © 1994 Wiley-Liss, Inc.     

Continuous positive airway pressure and lung inflation in sleep apnea patients.

BACKGROUND: It was shown in normals that an important decrease in upper airway resistance can be obtained with continuous positive airway pressure (CPAP). It was suggested that lung inflation in patients with sleep apnea syndrome (SAS) could also be a mechanism of action of CPAP. OBJECTIVE: In the present study we wanted to evaluate the effects of nocturnal CPAP on the daytime lung function pattern in patients with SAS. METHODS: We measured arterial blood gases and possible changes in static lung volumes in 57 SAS patients (37 with normal lung function, 10 with COPD and 10 with restrictive lung disease) after at least one month of CPAP therapy. RESULTS: A significant increase in PaO(2) (from 79 to 84 mm Hg, p = 0.01) and a decrease in AaDO(2) (from 23 +/- 1 to 16 +/- 1, p < 0.01) was only observed in SAS patients with normal lung function. This improved gas exchange was parallelled by a small but non significant change in the FRC (from 96.5 +/- 3.2 to 105.4 +/- 3.7%pred, p = 0.07) and TLC (from 101.3 +/- 1.7 to 104.1 +/- 1.4%pred, p = 0.15). Similar changes in TLC and FRC were also observed in SAS patients with obstructive and restrictive lung disease. CONCLUSIONS: Chronic nocturnal CPAP therapy can improve daytime gas exchange and may influence lung inflation during the daytime. The small changes seem to be a functional effect but of no clinical relevance.     

Effects of vitamin C on airway responsiveness to inhaled histamine in heavy smokers

Histamine bronchial threshold, the provocation concentration of histamine causing a 25% fall in maximal expiratory flow at 50% of forced vital capacity from the control value (PC25MEF50), was measured in seven heavy smokers and in seven sex- and age-matched nonsmokers before and one hour after ingestion, double-blind, of vitamin C (2 g) or placebo. Smokers had significantly lower baseline values of serum ascorbate, maximal expiratory flow at 50% of forced vital capacity (MEF50) and PC25MEF50: the latter was negatively related to serum ascorbate (r = -0.85; p less than 0.001). Acute treatment with vitamin C produced a significant decrease in PC25MEF50 in smokers (95% confidence limit (CL) from 4.87-3.36 to 2.91-2.01 mg.ml-1; p = 0.017), whilst it had no effect in nonsmokers. A preliminary open study on the effect of prolonged administration of vitamin C (1 g daily) was performed in smokers. One week of treatment produced a further significant decrease in PC25MEF50 (p less than 0.0001). Our results suggest that in heavy smokers histamine bronchial responsiveness may be attenuated by chronic ascorbate deficiency. In these circumstances, acute and short-term treatment with vitamin C may increase the bronchoconstrictive response to inhaled histamine.     

可必特对伴气道阻塞支气管扩张症急性期患者的疗效观察

目的 探讨可必特雾化吸入剂对伴气道阻塞的支气管扩张症急性期患者的治疗作用.方法 回顾性分析86例急性期支气管扩张症住院患者,入院时行肺功能提示不可逆性气道阻塞.对照组39例接受常规抗感染化痰等治疗,可必特治疗组47例,在常规治疗基础上加用可必特2.5 ml q6h氧气雾化,疗程1周.治疗前后评估2组临床症状评分,肺通气功能变化、疗效判定、不良反应差异.结果 治疗组经可必特治疗1周后临床症状评分由6.4±1.6降至2.2±1.0,对照组经常规治疗后临床症状评分由6.0±1.7降至2.8±1.5,各组患者经治疗后临床症状均明显好转（t值分别为10.2和15.5,P＜0.01）.治疗后可必特组临床症状评分2.2±1.0低于对照组2.8±1.5,二组比较差异有统计学意义（t =2.33,P＜0.05）.可必特治疗组肺通气功能FEV1％pred由治疗前（45.26±4.72）％升至（47.14±5.49）％;治疗总有效率为93.6％,平均住院天数8.2d,不良反应发生率为2.1％;对照组FEV1％pred由治疗前（48.01±5.46）％升至（51.62±4.23）％,治疗总有效率为89.7％,平均住院天数9.7d,不良反应发生率为2.6％.治疗组和对照组在肺通气功能、治疗疗效和不良反应方面差异均无统计学意义.结论 短期使用可必特对存在气道阻塞的急性期支气管扩张患者肺功能改善不明显,但在治疗过程中具有舒张气道,促进排痰、减轻临床症状的作用.     

Beclomethasone diproprionate reduced airway inflammation without adrenal suppression in young children with cystic fibrosis: a pilot study

Inhaled corticosteroids are commonly used in cystic fibrosis (CF), but there are few studies evaluating their safety in young children. We, therefore, prospectively administered beclomethasone diproprionate (BDP) to 12 clinically stable young children with CF to examine the safety of this therapy with respect to adrenal suppression and airway infection. To determine potential mechanisms of corticosteroid action in CF, we also examined airway markers of inflammation before and after inhaled steroid treatment. BDP 210 microg twice a day was given via spacer for 2 months. Twelve-hour serum and urine cortisols and response to low-dose synthetic ACTH cortisol stimulation were assessed. Bronchoalveolar lavage fluid (BALF) was examined pre- and posttreatment with BDP by quantitative bacteriology and indices of airway inflammation, including levels of total neutrophils, neutrophil elastase-alpha-1 antiprotease complexes (NEAP), CA 19-9 mucin-associated antigen, interleukin-8 (IL-8), and macrophage IL-8 mRNA. Following 2 months of treatment, serum and urine cortisol levels were unchanged. Response to low-dose ACTH cortisol stimulation was not significantly decreased at 30 min. Posttreatment BALF bacterial density was not statistically different from pretreatment; however, one patient who was initially culture negative became culture-positive with Hemophilus influenzae. BALF total neutrophil counts, corrected for epithelial lining fluid dilution, were decreased to approximately one third of pretreatment values (P = 0.03). NEAP and CA 19-9 mucin-associated antigen demonstrated similar decreases. BALF IL-8 levels and macrophage IL-8 mRNA levels were not statistically changed. These findings suggest that treatment with BDP 420 microg per day for 2 months in young children with CF does not affect urine and blood cortisol, causes no decrease in adrenal reserve, and does not result in a clinically significant increase in airway infection. In addition, the fall in bronchoalveolar lavage fluid inflammatory markers following BDP suggests possible modulation of neutrophil influx into the CF airway and provides justification for further studies of inhaled corticosteroids in CF.     

Nitrogen redox balance in the cystic fibrosis airway: effects of antipseudomonal therapy

Denitrifying bacteria metabolize nitrogen oxides through assimilatory and dissimilatory pathways. These redox reactions may affect lung physiology. We hypothesized that airway colonization with denitrifying bacteria could alter nitrogen balance in the cystic fibrosis (CF) airway. We measured airway nitrogen redox species before and after antimicrobial therapy for Pseudomonas aeruginosa in patients with CF. We also studied ammonium (NH(4)(+)) and nitric oxide (NO) metabolism in clinical strains of P. aeruginosa in vitro and in CF sputum ex vivo. Ammonium concentrations in both sputum and tracheal aspirates decreased with therapy. Nitric oxide reductase (NOR) was present in clinical strains of P. aeruginosa, which both produced NH(4)(+) and consumed NO. Further, NO consumption by CF sputum was inhibited by tobramycin ex vivo. We conclude that treatment of pseudomonal lung infections is associated with decreased NH(4)(+) concentrations in the CF airways. In epithelial cells, NH(4)(+) inhibits chloride transport, and nitrogen oxides inhibit amiloride-sensitive sodium transport and augment chloride transport. We speculate that normalization of airway nitrogen redox balance could contribute to the beneficial effects of antipseudomonal therapy on lung function in CF.     

Acapella versus 'usual airway clearance' during acute exacerbation in bronchiectasis: a randomized crossover trial

Devices such as the Acapella may facilitate independent airway clearance, however, few clinical trials have investigated the efficacy of Acapella. The aim of this study was to compare the effectiveness of Acapella to 'usual airway clearance' in adults during an acute exacerbation of bronchiectasis requiring oral antibiotic therapy. Twenty patients with bronchiectasis and an acute exacerbation requiring oral antibiotic therapy were recruited into a randomized crossover trial. Patients were allocated to one of two groups determined by concealed computer generated randomization. Group 1 (n=10): airway clearance session using Acapella at home twice daily during oral antibiotic therapy. Group 2 (n=10): 'usual' airway clearance sessions at home during oral antibiotic therapy. Patients recorded duration of each treatment session, volume of sputum produced and perception of breathlessness. An independent assessor performed outcome measures of spirometric lung function, pulse oximetry and breathlessness at the beginning and end of the study period. The mean volume of sputum expectorated during Acapella sessions was greater than for usual airway clearance sessions although this difference was not significant 2.61 ml (95% CI-1.62 to 6.84). Mean duration of Acapella sessions was greater than usual airway clearance sessions and approached significance. There were no significant between group differences in changes in lung function. This study demonstrates that the Acapella device may offer an acceptable, user-friendly method of airway clearance in patients with bronchiectasis.     

Serum vascular endothelial growth factor is elevated in cystic fibrosis and decreases with treatment of acute pulmonary exacerbation

Chronic bacterial infection and neutrophilic inflammation characterize cystic fibrosis (CF) pulmonary disease. In many disorders, inflammation and angiogenesis are codependent phenomena. We previously noted excessive angiogenesis in CF tissues and elevated vascular endothelial growth factor (VEGF) in random serum samples from subjects with CF. To further explore this finding, we measured serum VEGF in 38 subjects with stable CF and in 25 subjects with other pulmonary diseases. Mean VEGF was elevated in both groups compared with reference values, but it was higher in CF: 403 +/- 280 versus 255 +/- 169 pg/ml, p = 0.02. VEGF was negatively correlated with FEV(1) in CF, r = -0.51, p = 0.007. To assess the effect of airway infection on VEGF, 10 subjects with CF were studied before and after intravenous antibiotic therapy for pulmonary exacerbation. VEGF levels decreased with antibiotic therapy, from 537 +/- 220 to 259 +/- 176 pg/ml, p = 0.001. We conclude that circulating VEGF is increased in subjects with CF and other inflammatory pulmonary disorders. In CF, VEGF elevation is related to airway infection. We speculate that increased circulating VEGF is related to chronic inflammation, which is robust in CF. Elevated circulating VEGF may result in tissue angiogenesis, furthering the progression of pulmonary disease.