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Correspondence
ABPA in adulthood: a CFTR-related disorder
  1. P Lebecque1,
  2. X Pepermans2,
  3. E Marchand3,
  4. A Leonard1,
  5. T Leal2
  1. 1Pediatric Pulmonology & Cystic Fibrosis Unit, Cliniques Universitaires St Luc Université de Louvain, Belgium
  2. 2Department of Genetics, Université de Louvain, Cliniques St Luc, Brussels, Belgium
  3. 3Department of Respiratory Diseases, Université de Louvain, Cliniques de Mont-Godinne, Yvoir, Belgium
  1. Correspondence to Patrick Lebecque, Pediatric Pulmonology & Cystic Fibrosis Unit, Cliniques Universitaires St Luc Université de Louvain, 10 avenue Hippocrate, 1200 Brussels, Belgium; patrick_lebecque{at}hotmail.com

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In Western countries, allergic bronchopulmonary aspergillosis (ABPA) in childhood is very unusual beyond the context of cystic fibrosis (CF). It is presumed to be different in adulthood, although three studies1–3 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 pancreatic 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 (n=13 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 (±SD) at the time of DNA sampling was 58.9 (±14.2) years. Bronchiectasis were present in 14/18 patients. Sweat chloride values between 40–59 mmol/l and 30–39 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.

Table 1

Relevant data and genetic findings in 18 adult patients with allergic bronchopulmonary aspergillosis (ABPA)

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 even more strikingly different (p<0.0001; OR 714, 95% CI 75 to 6797).

This study considerably extends previous findings by demonstrating a strong link between ABPA in adults and CFTR mutations. Although not altering the message, limitations of this work include the small population size which is inherent to the rarity of ABPA, the absence of DNA testing in parents and the dilemma of the clinical relevance of putative CFTR mutations. The hitherto best studied CFTR-related disorders are congenital bilateral absence of the vas deferens (CBAVD) and idiopathic chronic pancreatitis (ICP). It has been estimated that 85% of patients with CBAVD and 30% of those with ICP carry at least one CFTR mutation while ∼50% and 10–15%, respectively, are compound heterozygous, with the F508del mutation and IVS8-T5 variant being most frequently detected.5 The present study supports the concept that ABPA in pancreatic-sufficient adults is a CFTR-related disorder, with rare class IV–V mutations being mostly found and IVS8-T5 not seeming to play a significant role. Moreover, as ABPA is usually associated with bronchiectasis, a major phenotypic feature of CF, appropriate investigations to exclude milder forms of CF are warranted in these patients.

References

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Footnotes

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval This study was conducted with the approval of the Ethics Committee of the Cliniques Universitaires de Mont-Godinne.

  • Provenance and peer review Not commissioned; not externally peer reviewed.

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