Cystic fibrosis is the most common lethal autosomal recessive disease. Mutations in a membrane protein cause secretions such as mucus and digestive juices to be abnormally thick and sticky.
Respiratory symptoms tend to dominate the course of the disease but other complications include gastrointestinal disorders, male infertility, osteoporosis, diabetes and rhinosinusitis.
Due to improved treatments in childhood, the life expectancy of patients with cystic fibrosis has increased. Doctors are now more likely to encounter adults with this disease so being aware of current and emerging therapies used in their management is important.
Cystic fibrosis is the most common lethal autosomal recessive disease and occurs in 1 in 2000 people. A defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which regulates the transport of chloride and other electrolytes, causes secretions to be abnormally thick and sticky. These secretions build up in the upper airways and the ducts of various organs affecting the lungs, gastrointestinal tract, pancreas, liver, sinuses, sweat glands and reproductive system. Respiratory problems, such as chronic infection and inflammation, tend to dominate the clinical course and a patient’s respiratory status ultimately determines their prognosis.
Managing respiratory disease
There are a number of respiratory complications including acute pulmonary exacerbations, asthma, haemoptysis, pneumothorax and pneumonia. Pseudomonas aeruginosa is the predominant organism, however other organisms may colonise the respiratory tract and warrant therapy on occasions.
Because sputum of increased viscosity will lead to worsening airway obstruction, patients are strongly encouraged to perform active airway clearance techniques such as autogenic drainage or positive expiratory pressure to maintain their health. A flutter device can be effective in some patients. This is a hand-held oscillating positive pressure device (see Fig. 1 ). The patient breathes out through the device against an alternating resistance. Back pressure leads to small airway opening which in turn promotes increased airway clearance.
Mucolytics are given to improve the viscosity of mucus and aid its clearance. Nebulised dornase alpha (2.5 mg) acts by breaking down DNA, which contributes to the high viscosity of the sputum.2 Responses are variable so patients can only continue this treatment on the Pharmaceutical Benefits Scheme if their lung function improves by 10% (forced expiratory volume in 1 second – FEV1 ) after a one month trial. There are very few adverse effects although haemoptysis has been reported.
Nebulised hypertonic saline, typically 5 mL of 6% solution twice a day, is also used to reduce mucus viscosity. The high salt content is thought to cause water to influx into the airway lumen and assist with mucus clearance. Many patients benefit from using this medication.3 However, some patients may not tolerate it because of severe bronchospasm or cough.
Inhaled mannitol powder has recently become available for cystic fibrosis.4 A standard dose is 400 mg twice a day. Its high sugar content elevates the osmolality within the airway leading to water influx into the lumen. Cough can be a limiting factor in adherence.
Fig 1 - Flutter device
Antibiotics are administered for several possible purposes:
- to eradicate or delay the onset of P. aeruginosa colonisation
- to maintain lung function
- to intensify treatment of a pulmonary exacerbation.
Eradication protocols contain intravenous antipseudomonal antibiotics followed by a prolonged course of nebulised colistin and oral ciprofloxacin.
Maintenance strategies include long-term treatment with oral azithromycin5 , 6 Nebulised tobramycin or colistin cycling over some months to years, and other oral antibiotics sometimes given in a rotating fashion, are commonly used. However, there is no evidence for this practice.
An exacerbation is difficult to define. One definition7 requires the patient to have two out of a possible seven symptoms – including fever, increased sputum volume (by 50%) and increased cough frequency (by 50%) as well as at least one of three additional clinical criteria such as a drop of 10% in forced vital capacity.
As the majority of adult patients are colonised with P. aeruginosa , therapies are directed at this organism. For mild exacerbations, oral ciprofloxacin (2 week course) and nebulised aminoglycoside (2–4 week course) are used. Typically, nebulised tobramycin 80–160 mg twice a day is given. Nebulised colistin (for example 1–2 million units twice a day) could be used as an alternative to tobramycin. This trial switch in therapy would be indicated if the patient was not responding to nebulised tobramycin or was intolerant (for example developing bronchospasm). Nebulised antibiotics rarely cause systemic adverse effects but with time can cause hearing impairment or balance problems in some patients.
If P. aeruginosa is not commonly isolated from the patient’s sputa, a course of dicloxacillin (for example 500 mg four times a day) for Staphylococcus aureuscolonisation or amoxycillin/clavulanic acid (for example 875/125 mg twice a day) may be used. Other pathogens that are sometimes isolated and need targeted therapy include Stenotrophomonas maltophilia (sulfamethoxazole/trimethoprim) and Haemophilus influenzae (amoxycillin).
For more severe exacerbations, patients are hospitalised and given intravenous antibiotics typically with a combination of a beta lactam-derived antibiotic (for example ticarcillin/clavulanic acid or ceftazidime) with an aminoglycoside (for example tobramycin as a single daily dose). The duration of these treatments is about 10–14 days. This empirical approach is justified as studies have shown that sputum sensitivities are not a useful guide to choosing therapy.8 Often the choice of drugs is dictated by previous allergies or intolerances of various antibiotics. Because deteriorating patients require frequent courses of these antibiotics, they should be closely monitored for long-term complications such as renal and hearing impairment.
Many patients regularly use short-acting bronchodilators, such as salbutamol, to aid airway clearance and enhance delivery of other inhaled drugs. Research on tiotropium, a long-acting anticholinergic, is just beginning.
Some patients with cystic fibrosis take these medications regularly to assist with asthma control or lung inflammation. Adherence and effectiveness are very variable. There is limited evidence for bacterial contamination of inhaler devices but it may occur.9
Rhinosinusitis is very common in cystic fibrosis and can be managed with a combination of saline sprays, inhaled steroids and sometimes oral prednisolone. Surgery may be required in some cases.
Managing gastrointestinal disorders
Patients can suffer from a range of gastrointestinal disorders including pancreatic insufficiency, liver disease (cirrhosis in 5% of patients), bacterial overgrowth and distal intestinal obstruction syndrome. About 15% of patients who are pancreatic sufficient can develop episodes of acute pancreatitis.
Most patients have pancreatic insufficiency and thus require lifelong enzyme replacement. This is titrated to the fat content in each meal or snack with the aim being to control symptoms of abdominal cramping pain and steatorrhoea and to maintain weight. A typical dose would be around 3–4 capsules with meals and 1–2 capsules with snacks, but this is highly variable.
Salt and fluids
Patients are strongly encouraged to take adequate salt and fluid throughout the whole year. Many patients take 4–8 salt tablets per day depending on the season. Fluids are generally electrolyte solutions (for example Glucolyte) with patients typically requiring 1–3 sachets per day.
Fat-soluble vitamins (namely vitamins A, D, E and K) are replaced by prescribing a combination therapy known as VitABDECK (2 tablets every morning).
The most commonly used oral nutritional supplement is Ensure which is available as 200 mL tetrapaks. A number of patients would take about 2–4 of these per day. Other options include Ensure Plus (contains increased calories), Sustagen, Resource and Scandishakes.
Calcium and bisphosphonates
Patients with cystic fibrosis are at increased risk of osteoporosis and many take oral calcium and additional vitamin D. Osteoporosis is monitored by bone mineral densitometry twice a year and is treated with bisphosphonates (and testosterone when appropriate).
Proton pump inhibitors
Gastro-oesophageal reflux is very common and often requires chronic therapy with a proton pump inhibitor.
A significant minority of patients need to administer nutritional supplements via a self-inserted nasogastric tube (usually about 1 L per night) to maintain their body weight. Gastrostomy is occasionally required instead.
A small percentage of patients with significant liver dysfunction are treated with ursodeoxycholic acid (500 mg twice a day) in an attempt to delay progression of liver disease to cirrhosis. However, evidence for this effect is lacking.
Many women with cystic fibrosis can conceive naturally and should be using contraception until they decide to try for a pregnancy. We recommend that they discuss their intentions with their doctor before attempting to conceive. Genetic counselling is also important for couples planning to start a family.
Pregnancy poses a number of challenges. Often women have an increased frequency of respiratory exacerbations as the pregnancy progresses. Nutrition is harder to maintain so often additional supplements are required. Gestational diabetes may occur.
Adherence to therapy
Patient survival has improved dramatically over a number of decades. However, new challenges are emerging because of antibiotic resistance and allergies. New treatments targeting the specific CFTR defect are becoming more available.
Conflict of interest: none declared
- Reid DW, Blizzard CL, Shugg DM, Flowers C, Cash C, Greville HM. Changes in cystic fibrosis mortality in Australia, 1979-2005. Med J Aust 2011;195:392-5.
- Jones AP, Wallis CE. Recombinant human deoxyribonuclease for cystic fibrosis. Cochrane Database Syst Rev 2003;3:CD001127.
- Elkins MR, Robinson M, Rose BR, Harbour C, Moriarty CP, Marks GB, 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;354:229-40.
- Jaques A, Daviskas E, Turton JA, McKay K, Cooper P, Stirling RG, et al.Inhaled mannitol improves lung function in cystic fibrosis. Chest 2008;133:1388-96.
- Wolter J, Seeney S, Bell S, Bowler S, Masel P, McCormack J. Effect of long term treatment with azithromycin on disease parameters in cystic fibrosis: a randomised trial. Thorax 2002;57:212-6.
- Saiman L, Anstead M, Mayer-Hamblett N, Lands LC, Kloster M, Hocevar-Trnka J, et al.Effect of azithromycin on pulmonary function in patients with cystic fibrosis uninfected with Pseudomonas aeruginosa: a randomized controlled trial. JAMA 2010;303:1707-15.
- Ramsey BW, Pepe MS, Quan JM,Otto KL, Montgomery AB, Williams-Warren J, et al. Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. Cystic Fibrosis Inhaled Tobramycin Study Group. N Engl J Med 1999;340:23-30.
- Foweraker JE, Laughton CR,Brown DF, Bilton D. Phenotypic variability of Pseudomonas aeruginosa in sputa from patients with acute infective exacerbation of cystic fibrosis and its impact on the validity of antimicrobial susceptibility testing. J Antimicrob Chemother 2005;55:921-7.
- Taylor CJ, McGaw J, Howden R, Duerden BI, Baxter PS. Bacterial reservoirs in cystic fibrosis. Arch Dis Child 1990;65:175-7.
- Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Dřevínek P, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011;365:1663-72.