Therapies which treat the underlying defect of cystic fibrosis (CF) are in development. But while these are awaited, current treatments must be used to their maximum potential in order to continue the upward trend in life expectancy of people with CF. The issues are discussed in a Seminar published Online First and in an upcoming edition of the Lancet, jointly authored by Dr Brian O'Sullivan, University of Massachusetts Medical School, USA, and Dr Steven Freedman, Harvard Medical School, Boston, USA.
CF is the most common lethal genetic disease in the white population, affecting some 1 in 3000 North Europeans and white Americans. It is rarer in Latin Americans and African Americans, and very rare in Africa and Asia. Thanks to improvements in treatment, life expectancy of CF patients has increased from 31 to 37 years in the past decade; and a UK model predicts that a child born with CF today will live to age 50. CF is caused by a mutation in the gene responsible for manufacture of a protein called cystic fibrosis transmembrane conductance regulator, or CFTR. Mutations of CFTR contribute to CF symptoms in various ways. These include dehydration of the airway surface, decreased airway lubrication, increased inflammation worsened by decreasing anti-inflammatory response, and conditions promoting bacterial growth – most notably for Psuedomonas aeruginosa.
The most reliable diagnosis of CF remains the sweat test. A chloride concentration of greater than 60 mmol/L in a person's sweat will mean a diagnosis of CF. The CFTR mutation can also be directly detected with various commercially available tests. Newborns are screened for CF by testing for levels of immunoreactive trypsinogen — of which a very high concentration implies pancreatic injury consistent with CF. Regions that use newborn screening now rarely see children present with symptoms (eg, lung problems, emaciation) at a much older age, since they have been 'caught' by the screening process.
Up to 90% of CF patients also develop 'pancreatic insufficiency', which can lead to greasy stools, abdominal pain and weight gain. It can also prevent absorption of 'fat-soluble' vitamins A, D, E, and K leading to problems such as anaemia, night blindness and osteoporosis. Virtually all men with classic CF are infertile, but women with the condition are fertile. Despite some controversy, the consensus is that women with adequate nutritional and lung reserves can successfully complete the term of pregnancy.
Despite the variety of symptoms CF presents, it is chronic airway infection and its consequences that lead to at least 80% of CF related deaths. Initial infection with P aeruginosa can be cleared by the patient though coughing or other physiotherapy strategies, or antibiotics. But eventually the bacteria form a film 'coat' that is difficult or impossible to clear with standard antibiotic treatment. Thus keeping patients free of P aeruginosa infection has a clear survival benefit, and heightened screening for this bacterium is now commonplace for CF patients in high-income countries. Other bacteria, including MRSA, can also infect the airways of CF patients.
The authors say that of the treatments available for CF, hypertonic saline, macrolide antibiotics, and ibuprofen deserve a special mention. Patients given 7% hypertonic saline via nebulisation have better lung function than those given standard saline, because it draws water into the airways and leads to sustained airway hydration, preventing infection. Azithromycin (a macrolide antibiotic) works by preventing P aeruginosa from forming films and killing it even within its films. It also has anti-inflammatory properties. Ibuprofen treatment seems to be most effective in younger patients (aged 5-13 years), ie, started before the development of inflammation and severe pathological changes in the lung. As well as these interventions, airway clearance techniques are used to clear airway secretions. These include percussion (chest massage), and special breathing devices which exert pressure. Nutrition is also key, with the authors saying: "The benefits of maintaining good nutrition in regard to long-term survival and lung health cannot be overstated." When pancreatic insufficiency occurs, supplements of both pancreatic enzymes and fat-soluble vitamins must be used.
New horizons for CF treatment are focussing on two classes of drugs in development. 'Correctors'* transfer more of the mutated CFTR from the cell's genetic machinery to its correct location on cell membranes, on the basis that is better to have much more partly-functioning CFTR in place than none at all. 'Potentiators' improve the function of CFTR at the cell membrane. The authors say: "A cocktail of a corrector and a potentiator might be the ultimate treatment for most patients with cystic fibrosis." Treatment which would correct the actual CFTR mutation — known as gene therapy — has so far been disappointing. This would work via insertion of one copy of normal DNA into the affected cells — but has met with problems due to the poor performance of vectors to transfer the DNA. Future development of new vectors and better methods of delivery are pre-requisites for gene therapy success. The authors say: "For now, however, the prospect of gene therapy remains a hope more than a reality."
The authors conclude: "The goal in 2009 is to preserve lung function by maximising current treatment regimens, so that patients can benefit fully from future therapies that could correct the basic defect and turn cystic fibrosis into a manageable disease."
Professor Brian O'Sullivan, University of Massachusetts Medical School, USA T) +1 508-856-4155 E) osullivb@ummhc.org
For full Seminar see: http://press.thelancet.com/cf.pdf
Notes to editors: *extra information from Professor O'Sullivan: "The potentiator VX-770 (Vertex Pharmaceuticals, Inc) has been through Phase 2b testing. The only corrector in trials I am aware of is another Vertex compound, VX-809. The results with VX-770 have been quite promising, whereas VX-809 is still in its infancy."
Journal
The Lancet