ABPA in adulthood: a CFTR-related disorder.

In Western countries, allergic broncho-pulmonary aspergillosis (ABPA) in childhood is very unusual beyond the context of cystic fibrosis (CF). It is presumed to be different in adulthood, although three studies 1e3 reported an increased frequency of cystic fibrosis transmembrane conductance regulator (CFTR) mutations in adults with ABPA. Out of the 63 patients investigated in these studies, none was reported as pancre-atic insufficient, all had sweat chloride values <60 mmol/l, only two carried the intron 8 splice variant 5T and a single patient was found to be compound heterozygous for two CFTR mutations. However, Miller et al studied only 10 patients and did not sequence all CFTR exons, while the two other reports, including one from our institution , were hampered by the small number of mutations initially looked for (n¼13 and 16, respectively). Accordingly, current guidelines for diagnosis of CF do not list ABPA as a suggestive phenotype feature nor even explicitly as a CFTR-related disorder. 4 We hypothesised that extending DNA analysis to the >1300 mutations currently considered as potential CF causing (http:// www.genet.sickkids.on.ca/cftr/app) would provide more accurate insights on the link between ABPA and CFTR in adulthood. The characteristics of the study group are detailed in the princeps paper. 2 DNA samples were no longer available for 3 out of the 21 original patient cohort, one of whom had been found to carry the R1162X mutation. Sequencing of all 27 CFTR exons, including flanking intronic regions, and a search for large rearrangements were undertaken in the remaining 18 DNA samples. Calling all the patients back for further familial genetic studies could not be considered and we assumed that two identified mutations are located in trans. ORs were calculated and proportions were compared with prior probability using the likelihood ratio test and assuming an expected carrier rate of 1/25 (4%) in the Belgian general population. Mean age (6SD) at the time of DNA sampling was 58.9 (614.2) years. Bronchi-ectasis were present in 14/18 patients. Sweat chloride values between 40e59 mmol/l and 30e39 mmol/l were observed in 1 (5.5%) and 6 patients (33%), respectively. A total of 18 putative mutations were identified in 17/36 alleles (table 1), most of which were mild/ uncommon. CFTR mutation carrier frequency was much higher in patients with ABPA (12/18, 67%) than expected in the general population (p < 0.0001; OR 48.0, 95% CI 5.2 to 445.3). The probability of bearing two CFTR mutations was …