In the 24 years since the cystic fibrosis (CF) gene was identified, the median life expectancy has risen from 25 to 39 years. Novel therapies are largely responsible for this progress, and there is hope that the pace will continue, as the first oral medications directed at correcting the gene defect have been approved by the FDA. However, it is still unclear how and when to pharmacologically treat this complicated patient population, especially during childhood.
Prior to the recent treatments developed by Vertex Pharmaceuticals, therapies for CF largely consisted of antibiotics, drugs to break up mucus secretions and chest physiotherapy. The new drugs, known as correctors and potentiators, partially “fix” the CF gene defect at the protein level, lowering the amount of chloride secreted in sweat and increasing lung function. At Boston Children’s Hospital, we continue to enroll large numbers of patients in Vertex’s clinical trials.
In the meantime, new data are informing the field. In the May 23 issue of The New England Journal of Medicine, a group from Australia published an important study, the Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF).
To truly appreciate the contributions of this study, we need to first understand the nature of CF. For patients with CF, the lining of the sinuses, aerodigestive tract, urogenital tract and sweat glands in the skin are lacking the CF gene, which regulates the concentration of sodium chloride. This leads to abnormal salt content and a thickening of the body’s mucus secretions. In some cases, bicarbonate in mucosal surfaces is abnormal, which leads to drying out of the mucus layer.
Abnormal salt content has different consequences in different organs. In the gastrointestinal tract, thick mucus can lead to blockage (called meconium ileus when present at birth). In the pancreas, digestive enzymes are not adequately hydrated, and the enzymes attack the pancreas directly, leading to pancreatic insufficiency and digestive problems. Infertility is a problem both for women, due to thickening of cervical mucus, and for males as a result of congenital bilateral absence of the vas deferens. The bile ducts of the liver are inadequately hydrated, which in rare cases leads to cirrhosis and liver failure.
The lung remains the cause for most of the morbidity and mortality in CF. Nationally, on average, patients have a decline of approximately 2.5 percent per year in lung function. CF lung disease has two phases. First, the surfaces of the nasal sinuses and bronchial tree become colonized with bacteria, most typically Staphylococcus aureus and Pseudomonas aeruginosa, forming a biofilm in the respiratory tract that antibiotics cannot completely eradicate.
Next, there is an immune response to the colonization—one that ironically worsens respiratory function. The principle soldiers in the battle, polymorphonuclear leukocytes (PMNs), or neutrophils, use an array of tools to kill bacteria. They then die, and their DNA stays behind and exacerbates the problem of viscous mucus. Further, the weapons used in the attack—including toxic oxygen species, hydrogen peroxide, hypochlorous acid (chlorox) and degradative enzymes—also attack and inflame the bronchial tissues. This pathological process is called bronchiectasis and eventually leads to respiratory failure. Its magnitude is directly tied to the pace of the disease.
While the new CF potentiator and corrector drugs are not expected to eradicate the bacteria, the normalized CF gene function in the lung could stop the progression of bronchiectasis. But if we could normalize the CF gene defect before the airways were colonized, the rate of progression of lung disease could be far lower.
The medication would be lifelong, and not a cure, much like insulin for diabetes. But unlike insulin, the CF drugs are man-made. Since children are not little adults, the drugs must not interfere with growth and development. So, how old should we be looking to treat children with the next generation of CF drugs?
That is the value of the AREST CF paper. The investigators prospectively followed 127 consecutive children diagnosed with CF at birth to track the development of bronchiectasis, performing chest CT scans and bronchopulmonary lavage (BAL) at 3 months and 1, 2 and 3 years of age. The prevalence of bronchiectasis was 29 percent at 3 months, increasing to 69 percent by 3 years of age. The major risk factors for progressing bronchiectasis were presentation with meconium ileus and respiratory symptoms at the time of CT and BAL.
The study authors noted that their observations set “the stage for trials of treatments that target activated neutrophils … in order to prevent or delay the onset of bronchiectasis in patients with cystic fibrosis.”
Although the study has limitations, it indicates that the beginnings of CF lung disease occur very early in life, suggesting the potential value of early treatment. Thus, the risk/benefit ratio of treating CF directly at the gene defect with oral drugs becomes extremely important—and for now, unquantifiable. Ongoing research will continue to assess when to intervene with treatment to delay the potentially effects of CF.