Long term effects of aerosolised rhDNase on pulmonary disease progression in patients with cystic fibrosis

Abstract

Background-After multiple studies, including clinical trials, suggested some mild clinical benefits from the use of rhDNase by patients with cystic fibrosis, a widespread acceptance of the drug has followed. However, long term eVects, specifically on lung disease progression, have not been demonstrated. Experience with the use of this drug in a single cystic fibrosis centre is presented and compared with the trends seen in the patient population of the centre before the introduction of the drug. Methods-Patients with cystic fibrosis routinely followed at the University of Minnesota Cystic Fibrosis Center and prescribed rhDNase for at least two years were included in this retrospective study. Data on spirometric parameters (FEV 1 and FEV 1 /FVC), allometric index, and admissions to hospital were retrieved from the centre's database for the two years preceding the prescription of rhDNase and the two years that followed. Trends in pulmonary function and allometric index were analysed by mixed linear modelling, and hospital admission rates for both periods were calculated and compared. Results-One hundred and ninety patients met the inclusion criteria for the study. In the two years preceding the prescription of rhDNase the trends noted were those of a mild decline in FEV 1 , a stable FEV 1 /FVC, and a mild improvement in allometric index. In the two years that followed the prescription of rhDNase a mild decline in all these parameters occurred which was a significant change from the previous period (all p <0.009). There was no diVerence between females and males in the trends experienced after the start of rhDNase. By logistic regression analysis only the presence of malnutrition at the time of prescription was associated with a positive trend after the introduction of rhDNase. No significant change in the hospital admission rates occurred, with rates of 0.52 (0.16) and 0.56 (0.21) admissions/patient/year for the periods before and after the prescription of rhDNase, respectively. Conclusions-The introduction of rhDNase to the regimen of patients with cystic fibrosis cared for at this centre has not been followed by a positive trend in lung function and nutritional parameters. There are some diVerences between this patient population and those who participated in previous studies which may help to explain the contrasting findings of this study. However, it is also possible that factors other than mucus clearance need to be improved to achieve a favourable response in disease progression. Patients on this treatment should be followed closely and the benefit judged on an individual basis. More studies are needed to define better the specific indications and use of this form of treatment.

DNase use in the daily care of cystic fibrosis: who benefits from it and to what extent? Results of a cohort study of 199 patients in 13 centres

“…Although several observational studies have been carried out to learn more about the long-term bene®ts of DNase [4,10,15], information regarding its use in daily practice is limited and there is no consensus on how to select patients for long-term treatment. Also, although several clinical trials have been carried out in patients with severe disease, results have been inconclusive [9,14].…”

Bronchial Hyperreactivity Related to Inhalation Therapy in Cystic Fibrosis Patients

“…Sixty-five out of 184 (35%) patients experienced 106 episodes of airway reactivity in response to nebulized rhDNase [45]. However, most studies did not demonstrate significantly more BHR, dyspnea, cough, wheeze and/or increased pulmonary obstruction in CF patients compared to controls (Supplementary Tables 1) [42,[46][47][48][49][50][51][52][53][54].…”

Rekombinante humane DNase (Dornase alfa) bei Mukoviszidose

“…Schwerkranke waren demgegenüber nach 12 Wochen rhDNase zu 22% und nach Plazebo zu 17% von einer 10%-igen FEV 1 -Reduktion betroffen [28]. Auch aus großen CF-Ambulanzen wurde von Verschlechterungen der pulmonalen Situation nach rhDNase berichtet: in der pädiatrischen Gruppe des Brompton-Hospitals [5] wurde bei 1/3 aller Kinder und in der Ambulanz in Minneapolis [29] 22-40% des Solls) wurde die Aktivität von Neutrophilenelastase und Cathepsin G vor, während und nach rhDNase-Therapie untersucht (Tabelle 1). Die Patienten waren chronisch mit Pseudomonas aeruginosa infiziert und hatten vor Therapiebeginn sehr hohe Elastaseaktivitä-ten.Es fand sich ein signifikanter Anstieg beider Enzyme nach 15-tägiger Inhalation von 1-mal 2,5 mg rhDNase, und eine Woche nach Beendigung der Therapie waren die Befunde wieder rückläufig.Die Befunde wurden dahingehend interpretiert, dass diese kationischen Proteasen, die zuvor an negativ geladene Polyanionen wie DNA gebunden waren, durch Therapie mit rhDNase freigesetzt wurden.Die Spaltung der DNA erhöhte so die schädliche proteolytische Aktivität im Sputum.…”