Case Report: When cystic fibrosis, elexacaftor/tezacaftor/ivacaftor therapy, and alpha1 antitrypsin deficiency get together.

In the last 10 years, the care of patients with cystic fibrosis (CF) has been revolutionized with the introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulator drugs, with a major impact on symptoms and life expectancy, especially considering the newest and highly effective elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) therapy. Conversely, adverse effects are relatively frequent, with some being life-threatening, such as severe hepatitis. Clinical trials on children starting CFTR modulators have reported transaminase elevations >3× upper limit of the norm in 10%-20% of patients, whereas real-life studies have reported discontinuation rates three times higher than those observed in phase 3 trials. We report the case of a 10-year-old boy with CF who developed severe acute hepatitis 2 weeks after starting ELX/TEZ/IVA therapy. An extensive screening for potential causes led to the identification of heterozygous alpha1-antitrypsin (AAT) deficiency with genotype MZ. The Z allele of SERPINA1 gene, encoding AAT, is known as a risk factor for CF liver disease. We hypothesized that it may act as a risk factor for drug-induced liver injury from CFTR modulators, notably ELX/TEZ/IVA. Therefore, checking AAT before starting CFTR modulator therapy can be suggested, in particular for children with previous, even transient, liver disease.

Allergic bronchopulmonary aspergillosis as an initial manifestation of cystic fibrosis: Diagnostic and therapeutic implications in the era of CFTR modulators.

Allergic bronchopulmonary aspergillosis (ABPA) results from complex hypersensitivity reactions to Aspergillus fumigatus, which often occur in patients with asthma, cystic fibrosis (CF), or CF transmembrane conductance regulator (CFTR)-related disorders. Genetic predisposition, particularly variants of the CFTR gene, probably plays a significant role in the development of ABPA. We present the case of a 20-year-old male with ABPA and bronchiectasis that was initially misdiagnosed as a result of normal sweat chloride values and negative first-level genetic testing results. Comprehensive CFTR gene sequencing revealed 2 pathogenic variants, R347H and D1152H, which together with the clinical phenotype and functional tests, supported the diagnosis of CF. Treatment with elexacaftor/tezacaftor/ivacaftor resulted in significant clinical and functional improvement, including a marked decrease in total IgE levels, suggesting a potential role for CFTR modulators in controlling ABPA. This case illustrates the evolving understanding of CF as a spectrum of disorders in which CFTR dysfunction may manifest subtly and variably, necessitating a high index of suspicion and a comprehensive diagnostic approach to ensure timely treatment in the era of highly effective CFTR modulators.

Lung structural and functional impairments in young children with cystic fibrosis diagnosed following newborn screening - A nationwide observational study.

BACKGROUND: Non-invasive and sensitive clinical endpoints are needed to monitor onset and progression of early lung disease in children with cystic fibrosis (CF). We compared lung clearance index (LCI), FEV1, functional and structural lung magnetic resonance imaging (MRI) outcomes in Swiss children with CF diagnosed following newborn screening. METHODS: Lung function (LCI, FEV1) and unsedated functional and structural lung MRI was performed in 79 clinically stable children with CF (3 - 8 years) and 75 age-matched healthy controls. Clinical information was collected throughout childhood. RESULTS: LCI, ventilation and perfusion defects, and structural MRI scores were significantly higher in children with CF compared with controls, but FEV1 was not different between groups. Lung MRI outcomes correlated significantly with LCI (morphology score (r = 0.56, p < 0.001); ventilation defects (r = 0.43, p = 0.001); perfusion defects (r = 0.64, p < 0.001), but not with FEV1. Lung MRI outcomes were more sensitive to detect impairments in children with CF (abnormal ventilation and perfusion outcomes in 47 %, morphology score in 30 %) compared with lung function (abnormal LCI in 21 % and FEV1 in 4.8 %). Pulmonary exacerbations, respiratory hospitalizations, and increase in patient-reported cough was associated with higher LCI and higher structural and functional MRI outcomes. CONCLUSIONS: The LCI and lung MRI outcomes non-invasively detect even mild early lung disease in young children with CF diagnosed following newborn screening. Pulmonary exacerbations and early respiratory symptoms were risk factors for structural and functional impairment in childhood.