Cystic Fibrosis (CF)


Cystic fibrosis (CF) is a genetic disease that results in lung infections and greatly impairs lung function.1 Mutations in the CF transmembrane conductance regulator (CFTR) gene affect CFTR protein function, rendering it unable to maintain chloride and sodium movement within physiological conditions. The lack of chloride on the cell surface results in less water being attracted and consequently thicker mucus.1,2 Symptoms of CF develop as these thick mucus secretions accumulate within the lungs and other organs, such as the pancreas and intestines.2 As the abnormal mucus blocks the airways, mucoactive drugs are used to improve airway clearance.3 Cystic fibrosis mucolytics are able to disrupt the mucus and reduce its viscosity and elasticity.4 These agents are therefore designed to reduce the thickness of the mucus so it can be more easily expelled.1 Mucolytics for CF should be inhaled and combined with airway clearance techniques to prevent infections and progressive damage to the lungs.1 

Two main types of mucus thinners are available for patients with CF, hypertonic saline and dornase alfa (Pulmozyme®). Current guidelines support the use of both agents in CF treatment, however, there are limited data available to suggest superior activity for either therapeutic approach.1,3 

Hypertonic Saline 

Hypertonic saline is a sterile saline solution with a concentration of 3%, 3.5%, or 7% sodium chloride that is used as cystic fibrosis mucolytic. The amount of salt in this solution attracts water into the airways so the mucus can become thinner and easier to remove.1 This solution also promotes the disruption of the ionic bonds of the mucus, helping reduce entanglements.3

The benefits in lung function with long-term use of hypertonic saline in CF have been demonstrated in a randomized trial involving 164 participants. The trial included adults and children with CF and reported that the hypertonic saline group maintained a significantly higher lung function during the follow-up period of 48 weeks than the placebo group. The study also revealed an increased quality of life in CF patients receiving hypertonic saline, as there were reductions in the frequency and duration of exacerbations with fewer days of absence from normal day-to-day activities and an easier airway clearance.5 

Hypertonic saline may be used in patients with CF who are at least 6 years of age and in patients with a forced respiratory volume (FEV1) equal or superior to 40%, depending on medical assessment.1

Dornase Alfa (Pulmozyme) 

Dornase alfa is a human recombinant deoxyribonuclease I (rhDNase) enzyme indicated for the management of CF in adult and pediatric patients.6 The mucus secretions in patients with CF contain high amounts of extracellular DNA released from leukocytes that have accumulated in response to infection. This DNA is cleaved by the DNase to help thin the mucus.1,6 Pulmozyme inhalation solution is developed by Genentech and can be administered using a jet nebulizer and an air compressor or a nebulizer system. The recommended dose of Pulmozyme when used as a cystic fibrosis mucolytic is one 2.5-mg single-use ampule inhaled once a day. 6 

dornase alfa (Pulmozyme)
Recombinant DNase I DNA cutting enzyme (dornase alfa), chemical structure. Used in the treatment of cystic fibrosis. Credit: Shutterstock

Several trials have been performed to compare dornase alfa to standard therapy, other medications, and placebo. A review of these studies and their respective outcomes has been recently published. Fifteen trials enrolling 2447 participants were performed to compare dornase alfa to a placebo or to no dornase alfa treatment. The efficacy of dornase alfa was also compared to those of hypertonic saline and mannitol. Data showed that participants using dornase alfa demonstrated significantly improved FEV1 compared to those receiving placebo at 1, 3, and 6 months and 2 years of trial duration. A decrease in pulmonary exacerbations was also reported in the trials with longer durations.7

The comparison of dornase alfa to hypertonic saline and mannitol showed no differences in the treatments, except for one trial that revealed an improvement in FEV1 in participants using dornase alfa compared to those receiving hypertonic saline. The combination of dornase alfa and mannitol did not result in increased benefits for the patients when compared to dornase alfa alone.7

The most common side effects observed with the use of dornase alfa include voice changes, pharyngitis, and rash.6

References

1. Mucus thinners. Cystic Fibrosis Foundation. Accessed January 6, 2022.

2. Cystic fibrosis. National Organization for Rare Disorders (NORD). Accessed January 6, 2022.

3. Shteinberg M, Haq IJ, Polineni D, Davies JC. Cystic fibrosis. Lancet. 2021;397(10290):2195-2211. doi:10.1016/S0140-6736(20)32542-3

4. Elkins MR, Bye PT. Mechanisms and applications of hypertonic saline. J R Soc Med. 2011;104(Suppl 1):S2-S5. doi:10.1258/jrsm.2011.s11101

5. Elkins MR, Robinson M, Rose BR, et al.; National Hypertonic Saline in Cystic Fibrosis (NHSCF) Study Group. A controlled trial of long-term inhaled hypertonic saline in patients with cystic fibrosis. N Engl J Med. 2006;354(3):229-240. doi:10.1056/NEJMoa043900

6. Pulmozyme®. Prescribing information. Genentech, Inc.; 2021. Accessed January 6, 2022.

7. Yang C, Chilvers M, Montgomery M, Nolan SJ. Dornase alfa for cystic fibrosis. Cochrane Database Syst Rev. 2016;4:CD001127. doi:10.1002/14651858.CD001127.pub3

Reviewed by Harshi Dhingra, MD, on 1/6/2022.