Impact of Elexacaftor-Tezacaftor-Ivacaftor on fungal colonisation in children and adolescents with cystic fibrosis.

BACKGROUND

CFTR modulators, such as elexacaftor/tezacaftor/ivacaftor (ETI), have markedly improved lung function in children with cystic fibrosis (cwCF). Their impact on fungal colonisation remains poorly investigated.

METHODS

We conducted an ancillary prospective study within the real-world observational study MODUL-CF of cwCF naïve to CFTR modulators and initiating ETI. Clinical and microbiological data were collected up to 12 months before (baseline) and at 1, 3, 6, and 12 months post-ETI. Fungal colonisation, particularly Aspergillus, and its clinical impact were compared between Aspergillus-colonised and non-colonised children.

RESULTS

A total of 238 cwCF from 26 centres were included. Fungal colonisation decreased from 59.2% to 47.0% (p<0.01), with a striking 61.0% reduction in Aspergillus fumigatus (p<0.001), whereas Candida albicans colonisation remained stable (32.4% vs. 31.5%). Furthermore, 83.1% of the 77 Aspergillus positive cwCF at baseline were Aspergillus-free by Year 2; 4 (5.2%) remained chronically and 7 (9.1%) transiently colonised. Conversely, 22 cwCF acquired Aspergillus colonisation during follow-up (n=13 in Year 1; n=9 in Year 2). At baseline, Aspergillus-colonised cwCF were older (13.6 vs. 11.7 years; p<0.001), had lower ppFEV₁ (79.5 vs. 86.3; p=0.017), and more pulmonary exacerbations (PEx) (2.79 vs. 1.81 /person/year; p<0.01) than non-Aspergillus colonised cwCF. Respiratory outcomes improved under ETI. Aspergillus colonisation was associated with a 57% higher PEx rate versus non-colonised cwCF in multivariate analyses (adjusted IRR 1.57, p<0.001).

CONCLUSIONS

ETI is associated with a sustained decline in A. fumigatus colonisation in cwCF. As early fungal colonisation may contribute to CF lung disease progression, its culture conversion under ETI contribute to improvement in PEx.