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 abno rmal rheology is partly due to the presence of high molecular weight d eoxyribonucleic acid (DNA). Recombinant DNase I human (rhDNase) has be en shown to depolymerise DNA and thereby reduce the in vitro viscoelas ticity of sputum in patients with cystic fibrosis. A phase II double b lind placebo controlled study showed that rhDNase improved pulmonary f unction in patients with cystic fibrosis. The object of the present st udy was to evaluate the in vivo effects of rhDNase on sputum rheology and to determine whether these were correlated with changes in pulmona ry function. Methods - Patients were randomised to receive either plac ebo or rhDNase 2.5 mg twice daily for 10 days. Sputum samples were col lected in sterile containers during screening and during treatment wit h the study drug. Pulmonary function and rheological analysis were the primary outcomes evaluated. Other parameters assessed were quantitati ve sputum bacteriology, sputum DNA concentration, and change in molecu lar 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 stor age 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 trea tment with rhDNase. These rheological parameters showed a correlation with forced expiratory volume in one second (FEV,) which was improved by a mean (SE) of 13.3 (5.6)% on day 10 of treatment with rhDNase comp ared with a change of 0.2 (3.1)% in the placebo group. There was no ch ange 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 pulmon ary function, one of the mechanisms being a reduction in the proportio n of high molecular weight DNA.