While new remedies are under way, current cystic fibrosis treatment must be optimized

While new remedies are under way, current cystic fibrosis treatment must be optimized

In a seminar published Online first and in a future edition of The Lancet the authors, Dr Brian O'Sullivan, from the University of Massachusetts Medical School, USA, and Dr Steven Freedman, at Harvard Medical School, Boston, USA discuss the issues of cystic fibrosis (CF) treatments. They both mention that there has been substantial progress in the development of new remedies treating the original defect of CF, but in the meantime, current treatments must be optimized in order to expand life expectancy of people with CF.

CF affects 1 in 3000 North Europeans and white Americans resulting in the most widespread deadly genetic disease. It is not common within Latinos and African Americans and even less common in Africa and Asia. In the past ten years there have been great improvements in treatments, resulting in the life expectancy of CF patients increasing from 31 to 37 years. A child born today with CF has a predicted life expectancy of 50 years. CF is caused by a mutation in the gene responsible for the development of a protein called cystic fibrosis transmembrane conductance regulator or CFTR. Mutations of CFTR contribute to CF symptoms in many ways such as dehydratation of the airway surface, a drop in airway lubrication, increased inflammation worsened by the reduction in anti-inflammatory response, and conditions promoting bacterial growth (especially Psuedomonas aeruginosa).

The sweat test is still the most dependable conclusion of CF, where a chloride concentration higher than 60 mmol/L in a person's sweat indicates a verdict of CF. Several commercial tests are also useful in detecting the CFTR mutation. Testing for levels of immunoreactive trypsinogen (elevated concentration suggests pancreatic injury typical of CF) is used to screen newborns for CF. As a result, there are far fewer children of an older age presenting symptoms (lung problems, emaciation) in the regions where there is newborn screening because they have been detected earlier in life.

'Pancreatic insufficiency' has been diagnosed in up to 90% of CF patients, and some of the symptoms are greasy stools, abdominal ache and weight increase. Pancreatic insufficiency can also prevent absorption of 'fat-soluble' vitamins A, D, E, and K leading to problems such as anemia, night blindness and osteoporosis. Practically all men with classic CF are infertile, but on the contrary, women remain fertile. Despite some debates, the consent is that women with sufficient nutritional and lung reserves can effectively complete a pregnancy.

80% of CF related deaths are due to chronic airway infection despite the variety of symptoms it can demonstrate. Initial infection with P aeruginosa can be contained by the patient through coughing, other physiotherapy approaches, or antibiotics. But in the long run the bacteria form a film 'coat' that is complicated or impossible to clear with customary antibiotic treatment. Thus maintaining patients free of P aeruginosa infection has clear benefits in increasing the survival rates, and therefore delicate screening for this bacterium is now common for CF patients in high-income countries. Other bacteria, including MRSA, can also infect the airways of CF patients.

The authors conclude that hypertonic saline, macrolide antibiotics, and ibuprofen are the most important remedies for CF. Patients treated with hypertonic saline via nebulisation have better lung function than those given only standard saline, as it attracts water into the airways resulting in a sustained airway hydration, thus preventing infection. Azithromycin (a macrolide antibiotic) helps in preventing P aeruginosa from forming films and killing them even within its films. It also has anti-inflammatory properties. Within younger patients, aged 5 to 13, ibuprofen treatment seems to be most effective, if started before the development of inflammation and severe pathological changes in the lung. Other important remedies include chest massages and special breathing devices exerting pressure in order to clear the airway secretions. Nutrition is also crucial, 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 takes place, pancreatic enzymes and fat-soluble supplement vitamins must be prescribed.

The future for CF treatment is focused on two types of drugs presently being developed. 'Correctors' transmit more of the mutated CFTR from the cell's genetic machinery to its correct location on cell membranes, assuming 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." Gene therapy has been unsatisfactory up to now to counteract the actual CFR mutation. This would involve the insertion of one copy of normal DNA into the affected cells. But the manipulation has given disappointing results due to the poor performance of the vectors to transfer DNA. Upcoming development of new vectors and improved methods of delivery are essential for the success of gene therapy. The authors write: "For now, however, the prospect of gene therapy remains a hope more than a reality."

"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," the authors say in conclusion.


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Section Issues On Medicine: Disease