The role of sweat chloride in determining CFTR protein restoration in people with cystic fibrosis.

Sweat chloride concentrations are elevated in people with cystic fibrosis due to the absence or dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, an epithelial cell membrane ion channel. For many people with cystic fibrosis with responsive variants and drug access, treatment with CFTR modulators increases CFTR function, reduces sweat chloride concentrations, and improves lung health and quality of life. In clinical trials, average sweat chloride reduction is correlated with clinical efficacy across different modulators and study populations. Thus, for people with cystic fibrosis, larger reductions and lower absolute sweat chloride concentrations are often presumed to indicate greater clinical response and better prognosis. However, although true at the population level, at the individual level, a relationship between sweat chloride and clinical outcomes has not been definitively shown. This Personal View highlights how sweat chloride quantification informs our understanding of CFTR modulator therapeutic response while cautioning its ability to fully predict individual clinical response.