Quantification of Phenotypic Variability of Lung Disease in Children with Cystic Fibrosis.

Mirjam Stahl,Eva Steinke,Marcus A Mall

doi:10.3390/genes12060803

Abstract

Cystic fibrosis (CF) lung disease has the greatest impact on the morbidity and mortality of patients suffering from this autosomal-recessive multiorgan disorder. Although CF is a monogenic disorder, considerable phenotypic variability of lung disease is observed in patients with CF, even in those carrying the same mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or CFTR mutations with comparable functional consequences. In most patients with CF, lung disease progresses from childhood to adulthood, but is already present in infants soon after birth. In addition to the CFTR genotype, the variability of early CF lung disease can be influenced by several factors, including modifier genes, age at diagnosis (following newborn screening vs. clinical symptoms) and environmental factors. The early onset of CF lung disease requires sensitive, noninvasive measures to detect and monitor changes in lung structure and function. In this context, we review recent progress with using multiple-breath washout (MBW) and lung magnetic resonance imaging (MRI) to detect and quantify CF lung disease from infancy to adulthood. Further, we discuss emerging data on the impact of variability of lung disease severity in the first years of life on long-term outcomes and the potential use of this information to improve personalized medicine for patients with CF.

Highlights

Cystic fibrosis (CF) is an autosomal-recessive multiorgan disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene on chromosome 7 [1,2,3,4]
We discuss current knowledge on factors leading to the broad phenotypic spectrum of CF lung disease, approaches for the quantification of Genes 2021, 12, x FOR PEER REVIEWthis variability of early lung disease severity and knowledge gaps3tohf 2a2t need to be addressed by future research to optimize personalized therapy for children with CF
Studies indicated neutrophilic inflammation associated with impaired lung function and lung function decline to be associated with the detection of Pseudomonas aeruginosa and Staphylococcus aureus [95]

Summary

Introduction

Cystic fibrosis (CF) is an autosomal-recessive multiorgan disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene on chromosome 7 [1,2,3,4]. Emerging evidence from several observational studies in infants and preschool children with CF diagnosed by newborn screening (NBS) suggests that CF lung disease starts in the first months of life with bronchial dilatation, air trapping, mucus plugging, ventilation inhomogeneity, neutrophilic inflammation and abnormal lung microbiota in often clinically unimpaired children [19,20,21,22]. These findings indicate that early therapeutic interventions may offer an opportunity to prevent or at least delay disease progression leading to irreversible lung damage. We discuss current knowledge on factors leading to the broad phenotypic spectrum of CF lung disease, approaches for the quantification of Genes 2021, 12, x FOR PEER REVIEWthis variability of early lung disease severity and knowledge gaps3tohf 2a2t need to be addressed by future research to optimize personalized therapy for children with CF

Methods

Results

Conclusion