Beyond postural drainage and percussion: Airway clearance in people with cystic fibrosis.

BACKGROUND: Evidence indicates that there are no statistically significant differences in effectiveness among the airway clearance techniques (ACTs) of active cycle of breathing, autogenic drainage, positive expiratory pressure (PEP) or oscillating PEP in the short-term, but are there differences in the long-term (one year)? The objective of the study was to demonstrate non-inferiority in the long-term. METHODS: Seventy-five people with cystic fibrosis entered the prospective, randomised controlled trial of these five different ACTs. The primary outcome measure was forced expiratory volume in one second (FEV(1)). Secondary outcome measures included exercise capacity and health related quality of life. RESULTS: Using intention to treat, data were available on 65 subjects at the end of the study period. There were no statistically significant differences among the regimens in the primary outcome measurement of FEV(1) (p=0.35). CONCLUSION: In different countries either one or several airway clearance regimens are used. This study provides evidence in support of current practices.

A case-controlled study with dornase alfa to evaluate impact on disease progression over a 4-year period.

BACKGROUND: Chronic endobronchial sepsis and profuse airway secretions dominate pulmonary disease in cystic fibrosis. Recombinant human DNase I (dornase alfa) reduces the viscoelasticity of airway secretions and hence may improve clearance of airway secretions. OBJECTIVES: To evaluate the long-term influence of dornase alfa on disease progression by performing a case-controlled study with dornase alfa over a period of 4 years. METHODS: A cohort of patients with cystic fibrosis who have been treated with dornase alfa were matched with a control group of patients with cystic fibrosis who had not received treatment with dornase alfa. The patients were matched by pulmonary function, age, and then sex. All available measurements of forced expiratory volume in one second (FEV1), height, weight and sputum bacteriology were collected for periods when the patients were free from respiratory exacerbations. RESULTS: Thirty-eight patients were matched. Slopes of median changes in FEV1 were -2.19 (-3.32, -1.06) in the control group and -0.75 (-1.87, 0.36) in the dornase alfa-treated group (p = 0.076). There were more infective exacerbations per patient year in the control group [3.13 (1.25-4.25)] in comparison to the dornase alfa group [1.25 (0.63-3.0), p = 0.035] over the 4-year treatment period. Antibiotic requirements were also greater with a median 43.75 (17.5-60.0) days of intravenous antibiotic use per patient year in the control group and 16.25 (8.5-44.0) days in the dornase alfa group (p = 0.034). CONCLUSIONS: The trends suggest that dornase alfa may have some influence on disease progression but in view of the limitations of the current study the need for further long-term studies in larger cohorts of patients is emphasised.

Nasal and exhaled nitric oxide is reduced in adult patients with cystic fibrosis and does not correlate with cystic fibrosis genotype.

STUDY OBJECTIVES: Inducible nitric oxide synthase (iNOS) is upregulated in a number of inflammatory lung conditions, and exhaled nitric oxide (NO) concentration is increased. However, previous studies in children with cystic fibrosis (CF) have shown that exhaled NO is reduced. The purpose of this investigation was to study exhaled NO concentration in adults with CF, and to investigate the effect of CF genotype and respiratory tract infection on this measurement. DESIGN: Exhaled and nasal NO levels were measured in 54 adult CF subjects and 37 healthy nonsmoking age-matched subjects using a chemiluminesence analyzer. Spirometry (FEV(1) and FVC), CF genotype, and bacterial colonization were also recorded. SETTING: This study was conducted at a national CF center. RESULTS: The mean age of patients was 26.9 years, and the mean FEV(1) was 50.5% predicted (range, 17 to 104%). Nasal NO in the CF patients (mean, 520 parts per billion [ppb]; confidence interval [CI], 452 to 588) was significantly lower (p < 0.001) than in control subjects (987 ppb; CI, 959 to 1,015). Exhaled NO was significantly lower (p < 0. 001) in CF patients (5.0 ppb; CI, 4.1 to 6.1) than in control subjects (7.3 ppb; CI, 6.8 to 7.8). FEV(1) did not correlate with nasal or exhaled NO. No association was observed between genotype and NO values or colonization with Pseudomonas aeruginosa. CONCLUSIONS: Despite the airway inflammation that is characteristic of CF, both nasal and exhaled NO were reduced. There was no association with genotype or infection status. As NO has bacteriostatic effects and may augment mucociliary clearance, this observation may be of clinical importance.

An evaluation of two aerosol delivery systems for rhDNase.

Increasingly, proteins are delivered to the respiratory tract as an aerosol, and clinical efficacy is dependent on optimal delivery of the protein in an intact form. The object of this study was to compare the in vivo and in vitro results of two aerosol delivery systems for the aerosolization of recombinant human deoxyribonuclease I (rhDNase) in patients with cystic fibrosis (CF). Patients with CF who were to be initiated on rhDNase were randomized either to the Hudson nebulizer and Pulmo-Aide compressor or to the Sidestream nebulizer driven by the CR50 air compressor. An in vitro study was performed in six sets of the two aerosol delivery systems. One hundred and seventy three patients were randomized in this open study, where rhDNase was administered for 7 days. Improvements in pulmonary function were observed in both groups following 1 week of therapy with rhDNase. Changes in the Sidestream/CR50 and Hudson/Pulmo-Aide groups, respectively, were: 16 and 11% for forced expiratory volume in one second (p=0.14); 12 and 10% for forced vital capacity (p=0.70); and 14 and 7% for forced expiratory flow at 25-75% of expiration (FEF(25-75)) (p=0.18). A greater proportion of patients in the Sidestream/CR50 group (58%) had a >10% response in FEF(25-75) compared to the Hudson/Pulmo-Aide group (42%; p=0.03). The Sidestream nebulizer had a faster nebulization rate (p<0.05), lower mass median diameter for the aerosol mass produced (p<0.001), higher percentage of particles in the respirable range (p<0.001) and greater respirable output (p<0.005), compared to the Hudson nebulizer. The Sidestream/CR50 combination is a quicker, more efficient system in vitro than the Hudson/Pulmo-Aide combination, whereas the in vivo study only suggested a difference. Clinically, the two systems have similar efficacy.

The effects of recombinant human DNase on neutrophil elastase activity and interleukin-8 levels in the sputum of patients with cystic fibrosis.

In cystic fibrosis (CF), neutrophil-dominated airway inflammation results in high levels of neutrophil elastase (NE). Some of these proteases are sequestered by the large amounts of deoxyribonucleic acid (DNA) present in purulent sputum. Recombinant human deoxyribonuclease (rhDNase), a new treatment in CF, depolymerizes DNA. Our concerns were that this might release proteases bound to DNA, which could be potentially harmful. The in vitro and in vivo effects of rhDNase on NE and interleukin-8 (IL-8) were evaluated. The acute effects of rhDNase were evaluated in CF patients during the first 6 days of treatment. Medium-term effects were evaluated in stable CF patients observed in rhDNase over 6 months. Sputum samples were collected at regular intervals and NE activity was measured by a fluorimetric assay and IL-8 with a radioimmunoassay. In vitro addition of rhDNase resulted in a twofold increase in protease activity and this was reflected in an acute transient rise on initiation of treatment with rhDNase. Medium-term treatment was associated with a decline in NE activity and IL-8. These in vivo results are encouraging, since the increase in protease activity was transient and the trend over 6 months was a reduction in both inflammatory markers.

In vivo effects of recombinant human DNase I on sputum in patients with cystic fibrosis.

BACKGROUND: Viscoelastic secretions in cystic fibrosis cause impaired mucus clearance and persistence of bacteria within the lung. The abnormal rheology is partly due to the presence of high molecular weight deoxyribonucleic acid (DNA). Recombinant human DNase I (rhDNase) has been shown to depolymerise DNA and thereby reduce the in vitro viscoelasticity of sputum in patients with cystic fibrosis. A phase II double blind placebo controlled study showed that rhDNase improved pulmonary function in patients with cystic fibrosis. The object of the present study was to evaluate the in vivo effects of rhDNase on sputum rheology and to determine whether these were correlated with changes in pulmonary function. METHODS: Patients were randomised to receive either placebo or rhDNase 2.5 mg twice daily for 10 days. Sputum samples were collected in sterile containers during screening and during treatment with the study drug. Pulmonary function and rheological analysis were the primary outcomes evaluated. Other parameters assessed were quantitative sputum bacteriology, sputum DNA concentration, and change in molecular mass of DNA polymers. RESULTS: The viscoelasticity of the sputum in untreated patients with cystic fibrosis was high and treatment with rhDNase reduced all the rheological parameters measured: dynamic storage modulus (a measure of elasticity), dynamic loss modulus (a measure of viscosity), and log complex modulus (a measure of mucus rigidity). The calculated cough clearance index was also improved following treatment with rhDNase. These rheological parameters showed a correlation with forced expiratory volume in one second (FEV1) which was improved by a mean (SE) of 13.3 (5.6)% on day 10 of treatment with rhDNase compared with a change of 0.2 (3.1)% in the placebo group. There was no change in bacterial colony counts or sputum DNA concentrations following treatment with rhDNase, but a small decrease in high molecular weight DNA was observed. CONCLUSIONS: Patients with cystic fibrosis treated with rhDNase show an improvement in rheological properties and pulmonary function, one of the mechanisms being a reduction in the proportion of high molecular weight DNA.

Two years experience with recombinant human DNase I in the treatment of pulmonary disease in cystic fibrosis.

Recombinant human DNase I (rhDNase) has been shown to improve pulmonary function in patients treated for up to 6 months. A cohort of 52 cystic fibrosis patients with a FVC > 40% predicted were enrolled into an open label study in order to evaluate longer-term effects of rhDNase. They received 2.5 mg rhDNase twice daily for 6 months followed by a 2-week wash-out period, and for the subsequent 18 months were treated with rhDNase once daily. Twenty-six male and 26 female patients with a mean FVC of 2.941 and FEV1 of 1.471 were recruited. Thirteen patients did not complete the study; there were seven deaths, three patients withdrew consent and three patients were lost to follow-up. Improvement in pulmonary function was seen following treatment and changes were evaluated as mean percent change from baseline. The maximum improvement occurred in the first month followed by a plateau at a lower level of improvement. The mean improvement in FEV1 over the first month was 13.3% (range 12-14.1%), followed by a plateau at around 7.1% (range 4.6-11.0%) for the subsequent 23 months. Mean FVC was improved by 12.03% (range 9.0-14.3%) over the first month and subsequently 4.2% (range - 2.2-10.2%). The effects on pulmonary function were similar for both treatment doses of rhDNase. There was also a steady improvement in weight from a mean of 54.2 kg to 55.7 kg at the end of the study.(ABSTRACT TRUNCATED AT 250 WORDS)

Recombinant human DNase I in cystic fibrosis patients with severe pulmonary disease: a short-term, double-blind study followed by six months open-label treatment.

Chronic pulmonary infection is the major cause of morbidity and mortality in cystic fibrosis (CF). Recombinant human deoxyribonuclease (rhDNase) in vitro has been shown to dramatically reduce the viscoelasticity of the sputum from CF patients. Phase II and III clinical trials have shown the drug to be safe, and that patients with a forced vital capacity (FVC) of > 40% predicted show an improvement in pulmonary function when receiving rhDNase. The current study evaluates the safety and efficacy of rhDNase in the most severly ill CF patients (FVC < 40% predicted). A double-blind, randomized, placebo-controlled trial in which patients received either 2.5 mg rhDNase twice daily or placebo for a period of 14 days followed by a 6 month open extension period (OEP) is reported. Seventy patients were recruited for the double-blind study, and 64 entered the OEP of whom 38 completed. During the OEP, all patients received 2.5 mg rhDNase twice daily. In both the double-blind period and the OEP the drug appeared to be safe. During the double-blind study, forced expiratory volume in one second (FEV1) and FVC improved in both groups but there was no statistically significant difference between the groups. In the OEP, there was mean improvement in percentage predicted FEV1 and FVC, 9 and 18%, respectively, for all patients participating. In conclusion, DNase is safe when administered in conjunction with a rigorous regimen of chest physiotherapy to severely ill patients (FVC < 40% predicted) with CF. The double-blind, 14 day study showed no significant improvement in pulmonary function but some patients may have improved after longer administration of rhDNase.

Medium term treatment of stable stage cystic fibrosis with recombinant human DNase I.

BACKGROUND: A phase II multicentre double blind placebo controlled study in 1993 showed that short term treatment (10 days) with recombinant human DNase I (rhDNase) was safe and improved pulmonary function in patients with cystic fibrosis with stable stage lung disease. A six month open label treatment study was conducted in some of the patients who participated in the short term study to assess the medium term effects of rhDNase. METHODS: Patients who completed the phase II study and were stable for 14 days prior to treatment were eligible. They were treated with rhDNase 2.5 mg twice daily for six months and reviewed at regular intervals to assess safety and efficacy. RESULTS: Fifty nine patients (31M,28F) of age range 16-55 years were recruited. Mean baseline values for forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) were 41.5% and 72.4% of predicted, respectively. The mean increase in FEV1 over the first month of treatment was 13.1% (range 12-14.1%) and then stabilised at 6.2% (4.6-7.8%) for the subsequent five months. FVC was similarly improved. Administration of rhDNase improved the severity of dyspnoea, cystic fibrosis related symptoms, and the modified Taussig/NIH score (not statistically significant). Fifty seven of the 59 patients completed the study; two died from progression of their pulmonary disease unrelated to treatment with rhDNase. The adverse events and intercurrent illnesses were no different from those expected in a cystic fibrosis population. Pharyngitis was the only possible drug related adverse event which occurred at least once in 14% of patients during the six month period. CONCLUSIONS: Administration of rhDNase was safe, well tolerated, and improved pulmonary function in patients with cystic fibrosis. When rhDNase was stopped at day 169 there was a deterioration in pulmonary function and dyspnoea score.