Effect of smaller droplet size of dornase alfa on lung function in mild cystic fibrosis

Abstract

Summary. Aerosolized recombinant human DNase (dornase alfa) reduces mucus viscoelasticity in vitro and improves pulmonary function in patients with cystic fibrosis (CF). We postulated that if dornase alfa could be delivered more peripherally to small airways in the lung in the form of smaller aerosol droplets in patients with early airway obstruction, the increase in pulmonary function from baseline might be improved. CF patients (n = 749) with mild lung disease (baseline forced vital capacity Ն70% predicted) were randomly assigned to receive dornase alfa 2.5 mg daily for 2 weeks by one of two nebulizer systems: 1) the Medic-Aid Durable SideStream nebulizer powered by the MobilAire Compressor (SS/MA) producing a droplet size with a mass median aerodynamic diameter (MMAD) of 2.1 µm; or 2) the Hudson T Up-draft nebulizer with a DeVilbiss Pulmo-Aide compressor (HT/PA) with an MMAD of 4.9 µm. Spirometry was performed at baseline and following 14 days of treatment.Dornase alfa delivered by both nebulizer systems produced small but statistically significant improvements in pulmonary function compared with baseline. There was a trend (P = 0.06) toward greater improvement in forced expiratory flow in 1 s in the SS/MA group (4.3%) compared with the HT/PA group (2.5%). These results indicate that the short-term spirometric response to dornase alfa is influenced in part by the physical characteristics of the aerosol in patients with mild lung disease. We speculate that this may be true for other therapeutic aerosols, and it appears that localization of disease in the lung plays a role in the response to inhaled agents. Pediatr. Pulmonol. 1998; 25:83-87.

Dornase alfa in early cystic fibrosis lung disease

“…The results of PEIT are consistent with previous studies, 14,16 and extend evidence of the efficacy of dornase alfa over a 2-year period to a group of patients with almost normal lung function, as evidenced by FVC and FEV 1 close to 100% predicted and FEF 25-75 in the lower normal range. Elsewhere in this issue, Tiddens presents evidence that even patients with mild lung function abnormalities, such as the subjects of the PEIT study, suffer from considerable architectural and functional impairment of the small pulmonary airways.…”

“…14 Subanalysis of the cohort of these patients with FVC > 85% predicted, 15 as well as a short-term study in 749 patients with FVC ! 70% predicted, 16 confirmed that results in patients with mild lung function abnormalities may be expected to be similar to those in the larger CF population. This conclusion was supported by 2-year data from the Epidemiologic Registry of Cystic Fibrosis (ERCF), 17 an observational study that raised the hypothesis that younger and milder CF patients may even benefit most from dornase alfa treatment.…”

“…This is hardly surprising, as lung volumes in these patients, being close to 100% of predicted values, can hardly be improved, and most of the lung damage is expected to be confined to the peripheral airways. A greater improvement in FEF 25-75 than in FEV 1 was reported previously with dornase alfa in relatively healthy patients, 16 but its importance has not been recognized until now. It indicates that dornase alfa treatment is capable of ameliorating the earliest signs of CF lung disease.…”

Editorial: Early Treatment With Dornase Alfa in Cystic Fibrosis: What Are the Issues?

“…In early stage disease, it is likely that treatment with dornase alfa will produce improvements in lung function that are either mere trends toward significance, or statistically significant, but clinically trivial. Such results are usually comfortably within the variability of the measurements for an individual, and that is precisely what has been shown by Geller et al 20,21 In any context, it is easy to describe a change that is statistically significant, but clinically trivial; and although it is conceivable that such small changes may mean that some underlying process has been favorably affected, the onus of proof that that is so is on those who assert the value of the measurements, and such observations will require protracted follow-up. Measurement of ''small airways disease'' has long been the Holy Grail of pulmonary physiologists, 29 and although many indices of flow and gas mixing have been proposed, 30,31 these airways, large in number and contributing little to airflow obstruction, may still undergo extensive destruction without giving a signal to the physiologist.…”

Small airway deposition of dornase alfa during exacerbations in cystic fibrosis; a randomized controlled clinical trial

“…Finally, we might speculate whether the particle size of 3 µm was small enough to reach the small airways. In a study by Geller et al, particles sized 2.1 µm were compared to particles of 4.9 µm and showed a trend ( P = 0.06) toward greater improvement in FEV 1 in the group using small particle size. Therefore, even smaller particles might be needed to reach the small airways.…”