Early Diagnosis and Intervention in Cystic Fibrosis: Imagining the Unimaginable

Abstract

Cystic fibrosis is the most common life-shortening genetic disease affecting Caucasians, clinically manifested by fat malabsorption, poor growth and nutrition, and recurrent sinopulmonary infections. Newborn screening programs for cystic fibrosis are now implemented throughout the United States and in many nations worldwide. Early diagnosis and interventions have led to improved clinical outcomes for people with cystic fibrosis. Newer cystic fibrosis transmembrane conductance regulator potentiators and correctors with mutation-specific effects have increasingly been used in children, and these agents are revolutionizing care. Indeed, it is possible that highly effective modulator therapy used early in life could profoundly affect the trajectory of cystic fibrosis lung disease, and primary prevention may be achievable.

Keywords: corrector; cystic fibrosis; cystic fibrosis transmembrane conductance regulator; immunoreactive trypsin(ogen); newborn screening; potentiator; sweat chloride test.

Figure 1

Early treatment with VX-770 prevents pathological changes in a cystic fibrosis animal model. (A) Effect of the CFTR potentiator VX-770 (ivacaftor) on ion channel gating of the CFTR G551D mutation. The G551D mutation abolishes ATP-dependent gating, which results in reduced channel open probability, but treatment with VX-770 alters activity of the mutant CFTR, leading to greater chloride ion and bicarbonate ion secretion, reduced sodium ion absorption, and hydration of epithelial surfaces. (B) Effect of prenatal and postnatal treatment with VX-770 (ivacaftor) on the airways of young ferrets with G551D mutation. Mucus accumulation, bacterial infection, and endobronchitis develop early in untreated airways of young kits with G551D mutations, but treated animals avoided bronchial infection and inflammation until the drug was discontinued. Similar effects were seen in other affected organs, including the pancreas, intestines, and genitourinary tract. Modified from Ferkol (65).