What Types of New Therapies are Available for Cystic Fibrosis?

Patient Presentation
A 10 day-old female came to clinic for her health supervision visit. She was breastfeeding well and her minimal jaundice had improved since her previous visit at 5 days of life. The parents and physician had been notified that her newborn screening test was positive for possible cystic fibrosis. The parents had been reassured that currently there was nothing specific to do for her but that a sweat chloride test would need to be completed for diagnosis. A pulmonary clinic appointment had already been made.

The past medical history showed a full-term infant without any concerns during the pregnancy and delivery. She was the second child for the married parents.
The family history was negative for cystic fibrosis or any lung diseases. There was diabetes and heart disease in older family members. The family was of northern European ancestry and the parents were not related. There were no miscarriages or infants with genetic diseases or who died young in either family.

The pertinent physical exam revealed a female who was 1% above her birth weight at 3765 grams, with a head circumference of 35 cm and length of 48 cm. All were around 50% for age. Her examination was normal.

The diagnosis of a normal female infant with an abnormal newborn screening test for possible cystic fibrosis was made. The pediatrician offered handouts that had been sent to her by the state newborn screening clinic about cystic fibrosis. The parents didn’t have many questions as they had already done some research online and had been re-assured by the newborn screening professional when they had called to tell them about the diagnosis. The patient’s clinical course showed that her initial sweat test was between 30-60 mmol/L but there had been an inadequate amount of sweat collected. A repeated test with adequate samples was normal.

Cystic fibrosis (CF) was identified in 1938 by Dr. Dorothy Andersen who described 49 patients with pancreatic insufficiency. Since that time significant achievements in the knowledge about the disease and treatments for patients have changed the mortality from a few months to patients living into middle adulthood or even later. Quality of life for patients and their families and friends has also markedly improved.

CF is the classic Mendelian autosomal recessive genetic disorder which is a worldwide disorder but affects people of north European ancestry more often where the main mutation is more common. There are more than 2000 variants, but the main mutation is known as Phe508del or F508del. This codes for the cystic fibrosis transmembrane conductance regulator gene (CFTR). Simplistically the CFTR codes for a protein that leaves the endoplasmic reticululum and attaches to the chloride and anion channel at the apical cell membrane which facilitates anion transport out of the cell. This regulates chloride, bicarbonate (needed for respiratory cell protection and pancreatic enzyme activation) and maintains epithelial surface hydration.

In countries with a high prevalence, newborn screening provides most of the diagnoses. Location specific protocols can include testing for immunoreactive trypsinogen, pancreatitis-associated protein testing and DNA mutation analysis. Newborn screening is a screening test and a sweat chloride test is considered the gold standard for diagnosis (> 60 mmol/L is abnormal). However there is a wide-variation in testing and in disease presentation, especially the older the patient is. Therefore CF should still be considered in the proper circumstances and in adults can include bronchiectasis, pancreatitis or infertility as presentations.

There are 7 classes of the CFTR mutation. “Class I, II, and III mutations are associated with no residual CFTR function and patients with these mutations on average have a severe phenotype, whereas individuals with class IV, V, VI mutations have some residual function of DFTR protein and have a mild lung phenotype and pancreatic sufficiency.” F508del is a class II variant. In the lung increased thick secretions along with infections and inflammation can cause lung damage as early as a few months. In the pancreas, increased mucus obstruction and inability to activate pancreatic enzymes can cause pancreatic insufficiency, malnutrition and diabetes (up to 40% of patients particularly females). Osteopenia and renal dysfunction and infertility are also potential problems. Infectious agents often colonize the lung and can cause disease and potentiate inflammatory responses. In children Haemophilus influenzae and Staphylococcus aureus are common. Over time, more gram-negative bacteria become prevalent and especially Pseudomonas aeruginosa are important to manage

Learning Point
Standard of care in high-income countries may be different than middle- and low-income countries because of available resources. Multi-specialty, designated care centers generally have the best outcomes but they are not always available. Patients should be referred for specialty care as soon as the diagnosis is made. Treatment for very young infants does make a difference in long-term outcomes as the effects of the disease appear to be additive over time. For pancreatic disease, a patient’s nutritional status is monitored closely and pancreatic enzyme replacement therapy completed daily. For lung disease, patients are encouraged to exercise which helps with pulmonary toilet. Specific pulmonary toilet physiotherapy is often initiated again to improve movement of secretions. Hypertonic saline inhalation is very effective in adults and data is also positive for children. Prophylactic antibiotics help prevent colonization and pulmonary infections. Regimens for this vary. Azithromycin is used as an anti-infective (especially against Pseudomonas aeruginosa) but has immunomodulatory activity as well.

Treating the underlying cause of CF appears to have made a significant leap in the past 2-3 years with trials of different modulator medications. For minimal function mutations where there is little function, medications are called “correctors” can be used which can be thought of as increasing the overall protein availability in some manner. For residual function mutations where some function is retained but is not overall effective enough, the medications are “potentiators” which can be thought of as improving the protein function in some manner. Combinations of these medications including “triple therapy” with ivacator (a potentiator), tezacaftor (a corrector) and elexacaftor (a corrector) can significantly improve lung functions. Other corrector medications are available including lumacaftor. Governmental approval of various drugs and combinations depends on location and also on specific CFTR variants. There is also the cost of these medications which currently is significant.

Patients’ whose disease leads to end-stage lung disease may be eligible for lung transplantation. Gene therapy is also being researched.

Questions for Further Discussion
1. How is cystic fibrosis managed in your location?
2. How are positive newborn screening results handled in your location?
3. What is the pediatrician’s role in rare or not so rare diseases? A review can be found here

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Cystic Fibrosis and Newborn Screening.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Elborn JS. Cystic fibrosis. The Lancet. 2016;388(10059):2519-2531. doi:10.1016/S0140-6736(16)00576-6

Doull I. Cystic fibrosis 2019: Year in review. Paediatr Respir Rev. 2020;35:95-98. doi:10.1016/j.prrv.2020.04.001

De Boeck K. Cystic fibrosis in the year 2020: A disease with a new face. Acta Paediatr. 2020;109(5):893-899. doi:10.1111/apa.15155

Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa