IMPACT OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR MODULATORS ON RESPIRATORY, NUTRITIONAL, AND INTESTINAL PARAMETERS IN CHILDREN WITH CYSTIC FIBROSIS: A SINGLE CENTER OBSERVATIONAL STUDY

Abstract

Highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulators have substantially changed the course of pediatric cystic fibrosis (CF) by improving CFTR function, respiratory outcomes, and nutritional status. The extent to which modulator therapy reverses severe exocrine pancreatic insufficiency and chronic low-grade intestinal inflammation in children remains incompletely defined. Aim: To characterize the multidimensional impact of CFTR modulator therapy on CFTR function, respiratory morbidity, nutritional status, exocrine pancreatic function, and intestinal inflammation in a real-world pediatric CF cohort. Materials and methods: In this prospective, single-center observational study (April 2024-January 2026), we included children aged 1-17 years with confirmed CF. The main treatment cohort comprised 32 genetically eligible children who initiated and maintained CFTR modulator therapy (ETI) for at least 12 months. Sweat chloride, anthropometric z scores, respiratory microbiology, liver function, and vitamin D status were assessed at predefined timepoints. In a digestive sub cohort of 31 treated children, fecal elastase, fecal calprotectin, and fecal neutrophil gelatinase-associated lipocalin (NGAL) were measured according to treatment duration and compared with values in 22 age matched healthy controls without digestive disease. Respiratory morbidity was evaluated from the frequency of infectious pulmonary exacerbations, airway microbiology, and lung function; spirometry was performed in children aged ≥6 years and ventilatory impairment was categorized as normal, mild, moderate, or severe. Results: After 12 months of CFTR modulator therapy, mean sweat chloride decreased from 114.1 to 78.3 mmol/L, indicating a marked improvement in CFTR function at cohort level. Weight for age and body mass index (BMI) z scores improved significantly, whereas height for age z scores remained essentially unchanged, consistent with a predominantly weight-driven short-term nutritional recovery. The mean annual rate of infectious pulmonary exacerbations declined from 4.72 at baseline to 0.41 at 6 months, reflecting a rapid and sustained reduction in respiratory morbidity. Diagnosis before 6 months of age was associated with a higher risk of severe exocrine pancreatic insufficiency and vitamin D deficiency, delineating an early onset, severe digestive phenotype. Conclusions: In children with CF, CFTR modulator therapy confers major clinical and biological benefits in terms of CFTR function, respiratory morbidity, and weight-related nutritional recovery. However, established severe exocrine pancreatic insufficiency and persistent low-grade intestinal inflammation appear only partially reversible, suggesting that the digestive phenotype of CF is less amenable to correction once structural damage has occurred. Incorporating fecal elastase and fecal inflammatory biomarkers into routine follow-up, alongside anthropometry, respiratory outcomes, and hepatic monitoring, may enhance multidimensional disease surveillance and more precisely guide long-term nutritional and hepatodigestive management in the era of highly effective CFTR modulators.