Burden of cystic fibrosis in children <12 years of age prior to the introduction of CFTR modulator therapies

Abstract

BackgroundCystic fibrosis (CF) is a genetic, multisystemic, progressive and life-shortening disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Different genotypes have been linked to variations in disease progression among people with CF. The burden of illness (BOI) in children with CF is incompletely characterised, particularly as it relates to CFTR genotypes prior to the availability of the first CFTR modulators. This retrospective, cross-sectional, descriptive study evaluated the BOI in US children with CF &lt;12 years of age prior to the first approval of CFTR modulators.MethodsData from the US Cystic Fibrosis Foundation Patient Registry from 2011 were used to summarise key patient and disease characteristics using descriptive statistics, overall and grouped by age (0 to &lt;2 years, 2 to &lt;6 years and 6 to &lt;12 years) and genotype (F508del/F508del, F508del/minimal function (MF), MF/MF, gating mutation on ≥1 allele, residual function mutation on ≥1 allele and R117H on ≥1 allele) group.ResultsThe analysis included 9185 children. Among 6-year-olds to &lt;12-year-olds, mean (SD) per cent predicted FEV1 in 1 s was 92.6% (17.5%). Among all children &lt;12 years of age, the mean (SD) all-cause hospitalisation and pulmonary exacerbation rates in 2011 were 0.4 (1.0) and 0.3 (0.8), respectively. Most (93.6%) had ≥1 positive lung microbiology culture. CF-related medication and nutritional supplementation use was common across all ages and genotypes. More than half (54.7%) had ≥1 CF-related complication. Evidence of disease burden was observed across the age and genotype groups studied.ConclusionsPrior to the approval of the first CFTR modulator therapies in children &lt;12 years of age, CF was associated with substantial BOI from an early age—including respiratory infections, hospitalisations/pulmonary exacerbations, need for supplemental nutrition and pharmacological treatments—irrespective of genotype.

A Phase 3, open-label, 96-week trial to study the safety, tolerability, and efficacy of tezacaftor/ivacaftor in children ≥ 6 years of age homozygous for F508del or heterozygous for F508del and a residual function CFTR variant

“…The observed PEx event rate was low (0.25/year) in this study and is lower than the rate reported for a large cohort of children of the same age range prior to initiating CFTR modulator therapy (0.4/year) [32] .…”

Elexacaftor/tezacaftor/ivacaftor in children aged 6–11 years with cystic fibrosis, at least one F508DEL allele, and advanced lung disease: A 24‐week observational study

“…1,2 However, the clinical consequences of CF often appear in early childhood and require aggressive symptomatic treatment with the aim of preserving lung function and maintaining adequate nutrition and growth. 3 Unfortunately, some children still develop severe lung disease despite intensive care in specialized CF centers: the Italian CF Registry showed that about 1% of 674 children aged 6-11 years had <40% of predicted forced expiratory volume in the first second (FEV 1 ) in 2020 (personal communication). Such cases are extremely difficult to manage and, when conventional treatment fails, the only alternative is lung transplantation.…”

Cystic fibrosis: candidate selection and impact of the cystic fibrosis transmembrane conductance regulator therapy

“…As ETI becomes more widespread, longer-term natural history studies are warranted to determine impact on lung function, disease progression, and referral for lung transplant. Prior to the approval of CFTR modulators, CF has been associated with a high burden of illness in children [49 ▪ ], and modulators are increasingly used prior to the development of significant lung disease. Short-term studies of ETI in children aged 6–11 have demonstrated similar clinical improvements to adults [50 ▪ ] and an open-label study of children aged 2–5 years is in progress (NCT04537793).…”