Recombinant DNase

Recombinant DNase

Jan, 2001. Recombinant DNase [online]. Seacroft and St James's University Hospitals, UK. Available from http://www.cysticfibrosismedicine.com

In 1990 Shak and colleagues cloned, sequenced and expressed a recombinant DNase 1 (rhDNase) and suggested that it may reduce the viscosity of CF sputum (Shak et al, 1990). The availability of nebulised rhDNase (Pulmozyme) represents an important advance in therapy for some patients (Bryson & Sorkin, 1994). DNA is derived from the nuclei of degenerating white blood cells, present in excess in the CF sputum. The addition of DNA to CF sputum increases its viscosity (stickiness), making it harder to clear sputum from the airways with physiotherapy or coughing. DNase is an enzyme which breaks down DNA. When DNase is inhaled through a compressor and nebuliser, the viscosity of CF sputum is significantly reduced.

Preliminary studies in 'mild to moderately affected' patients (FVC > 40% predicted normal) confirmed that nebulised rhDNase was safe and effective, resulting in improved sputum clearance, better respiratory function and an increased sense of well-being (Aitken et al, 1992; Hubbard et al,1992). FEV1 increased within a few days of starting treatment, but rapidly fell to baseline levels when rhDNase was withdrawn. Subsequent trials confirmed these positive effects (Ranashina et al, 1993; Fuchs et al, 1994; Shah et al, 1995; Harms et al, 1998; Henry et al, 1998). Treated patients also had a reduced need for additional antibiotic treatment (Fuchs et al, 1994). Long term studies have shown that improvements in respiratory function are maintained for at least 2 years (Shah et al, 1995). Trials in more severely ill patients have also shown a positive effect on respiratory function with inhaled rhDNase, although longer term therapy may be needed to realise this (Hodson, 1995). Side effects have been limited to hoarseness of the voice in a minority of patients, and the drug is well tolerated by patients with all degrees of chest involvement (Fuchs et al, 1994; Hodson 1995).

Although treatment was initially targeted at patients with chronic P. aeruginosa infection, recent research in children aged six years and over, with or without chronic P. aeruginosa infection, has shown improved respiratory function after two years rhDNase treatment compared to placebo.

A daily dose of 2.5 mg appears to be adequate for most patients. It is essential that rhDNase is not mixed with any other drug in the nebuliser chamber. It should not be taken within half-an-hour of an inhaled antibiotic as the latter may denature the protein structure of rhDNase, and not less than half-an-hour before chest physiotherapy. The optimal nebuliser compressor system appears to be a Sidestream/CR50 combination (Medicaid). More experience will determine the optimal way to use the drug.

A consensus document issued by the United States CF Foundation suggests that the majority of CF patients have some degree of inflammation in their airways (i.e., cough or sputum production) and warrant a trial of inhaled rhDNase (Ramsey & Dorkin, 1993). The early trials showed a significant increase in mean FEV1 values but, on closer examination of the results, there was a wide variability in individual patient responses. About 6% of patients showed a fall in respiratory function with Pulmozyme. Further experience with the drug has confirmed the unpredictability of patient responses. In the paediatric unit at the Royal Brompton hospital a third of children showed a greater than 20% increase in FEV1 after treatment with Pulmozyme for one year but a third of children showed a fall in respiratory function. Other units, including Leeds, have had similar experience. Importantly, some of the children with worse respiratory function said that they felt better (Davies et al, 1997). There is unfortunately no way of pre-determining responders.

All patients receiving rhDNase must be properly monitored, preferably by CF Centre teams. In view of the expense of Pulmozyme and the fact that only a proportion of patients will respond to it, it is necessary to follow closely all patients receiving this treatment and to judge its efficacy in each individual case. As highlighted in the Brompton study, merely feeling better is not enough (Bush, 1998). In Leeds the effect of rhDNase in all patients who have evidence of endobronchial inflammation such as cough or sputum production is carried. The evidence based prescribing practice regimen from Roche is used. All patients receive one month of Pulmozyme therapy and are monitored before and after this treatment. An improvement of 10% or greater in respiratory function is taken to indicate a positive response. These patients continue with their treatment and the month's trial is funded by the hospital. However, Roche reimburses the hospital for the cost of the months trial for all patients who fail to show response.

All patients receiving Pulmozyme are continually monitored to ensure continuing efficacy thereafter. This protocol may not work for adult patients with more severe disease who may need a longer trial of therapy in order to show a positive effect. In Leeds such patients are given a three to six month trial of Pulmozyme.

We still, perhaps, do not know the optimal way to use Pulmozyme. Some physicians have raised questions about its long term effect. Milla, reporting results from a large North American CF Centre, showed that respiratory function decreased more in the two years after starting Pulmozyme therapy than in the two years preceding, and there was no change in hospital admission rate (Milla, 1998). Zach suggested that Pulmozyme may be just a cosmetic treatment, masking an on-going destructive process in the lungs. When treatment was stopped patients respiratory function actually fell below their previous baseline (Zach, 1996). Continuing improvements in lung function tests after two years of rhDNase may coexist with deteriorating High Resolution CT scan appearances in some patients. Improvement of lung function may therefore not prevent on-going lung destruction (Roos-Liegmann et al, 1999). On the other hand Geller showed that Pulmozyme improves lung function in patients with mild lung disease and near normal function (Geller, 1997), and Rittie showed prevention of pulmonary deterioration in most patients over four years of treatment (Rittie et al, 1999).

In clinical practice rhDNase appears effective over at least 12 months, treated patients showing a mean 4% increase in FEV1 compared to a 1.6% fall in the untreated cohort in a large observational study (Johnson et al, 1999). In summary, Pulmozyme is an effective additional treatment for a large number of patients with cystic fibrosis. Patients receiving Pulmozyme must be monitored for continuing evidence of response. Definitive studies are needed to examining long term gains for the patient and for the NHS in terms of possible cost savings in other areas of treatment. Unfortunately, the opportunity to do this through a randomised controlled trial has been lost as so many of the potential beneficiaries of Pulmozyme therapy are already receiving this treatment. Lastly, there is some evidence that combining hypertonic saline and Pulmozyme maximises improvement in cough clearance (King et al, 1997).

References

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