Background: The combination of elexacaftor–tezacaftor–ivacaftor modulators (ETI) has improved clinical outcomes for people with cystic fibrosis (pwCF). Objectives: This study aimed to evaluate changes in nutritional and morphofunctional assessments, as well as anxiety, depression symptoms, and quality of life, in pwCF after starting ETI therapy. Methods: This was a prospective observational study. We measured body composition (fat mass [FM] and fat-free mass [FFM]) using bioelectrical impedance analysis (BIA) and skinfold thickness measurements (SMs). We also assessed hand grip strength, dietary intake via surveys, blood and stool biomarkers, symptoms of anxiety and depression using the Hospital Anxiety and Depression Scale [HADS], and quality of life through the Cystic Fibrosis Questionnaire—Revised (CFQR). Results: A total of 31 pwCF were evaluated. Significant improvements were observed in respiratory function and quality of life, alongside an average weight increase of approximately 5 kg (60% FM and 40% FFM). The prevalence of malnutrition, based on BMI and the FFM index, decreased significantly, while the rate of overweight/obesity increased. Biomarker analysis indicated better nutrient absorption and reduced intestinal inflammation, as evidenced by significant changes in faecal calprotectin, nitrogen, and fat levels, as well as blood lipid and vitamin profiles. Conclusions: Despite a reduction in caloric intake, an increase in weight was observed one year after initiating ETI. This increase was attributed to gains in both FM and FFM, suggesting improved metabolic efficiency and nutrient absorption. Both SM and BIA were found to be useful assessment tools. These findings indicate the need to modify the nutritional approach, focusing on the quality rather than the quantity of intake, and aiming for an appropriate body composition (FFM) rather than solely focusing on BMI.
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