Mutations that permit residual CFTR function delay acquisition of multiple respiratory pathogens in CF patients

Abstract

Background: Lung infection by various organisms is a characteristic feature of cystic fibrosis (CF). CFTR genotype effects acquisition of Pseudomonas aeruginosa (Pa), however the effect on acquisition of other infectious organisms that frequently precede Pa is relatively unknown. Understanding the role of CFTR in the acquisition of organisms first detected in patients may help guide symptomatic and molecular-based treatment for CF.

Methods: Lung infection, defined as a single positive respiratory tract culture, was assessed for 13 organisms in 1,381 individuals with CF. Subjects were divided by predicted CFTR function: 'Residual': carrying at least one partial function CFTR mutation (class IV or V) and 'Minimal' those who do not carry a partial function mutation. Kaplan-Meier estimates were created to assess CFTR effect on age of acquisition for each organism. Cox proportional hazard models were performed to control for possible cofactors. A separate Cox regression was used to determine whether defining infection with Pa, mucoid Pa or Aspergillus (Asp) using alternative criteria affected the results. The influence of severity of lung disease at the time of acquisition was evaluated using stratified Cox regression methods by lung disease categories.

Results: Subjects with 'Minimal' CFTR function had a higher hazard than patients with 'Residual' function for acquisition of 9 of 13 organisms studied (HR ranging from 1.7 to 3.78 based on the organism studied). Subjects with minimal CFTR function acquired infection at a younger age than those with residual function for 12 of 13 organisms (p-values ranging: < 0.001 to 0.017). Minimal CFTR function also associated with younger age of infection when 3 alternative definitions of infection with Pa, mucoid Pa or Asp were employed. Risk of infection is correlated with CFTR function for 8 of 9 organisms in patients with good lung function (>90%ile) but only 1 of 9 organisms in those with poorer lung function (<50%ile).

Conclusions: Residual CFTR function correlates with later onset of respiratory tract infection by a wide spectrum of organisms frequently cultured from CF patients. The protective effect conferred by residual CFTR function is diminished in CF patients with more advanced lung disease.

Figure 1

Unadjusted Kaplan-Meier (K-M) plots for 12 of 13 infectious organisms studied. Gray lines represent 'Minimal' CFTR function subjects and black lines represent subjects with 'Residual' CFTR function. There are differing numbers of subjects used in each plot due to the inclusion criteria of having a previous negative culture prior to the first positive culture for the particular organism. Median age differences are presented for those infections not affected by censoring, otherwise ages corresponding to the point where 25% of the population is affected is presented. Corresponding t-tests for the unadjusted K-M and Cox proportional hazard ratios with 95% confidence interval adjusted for the FEV₁BeforeInfx and the number of cultures per subject per year are presented. A. Pseudomonas aeruginosa. B. mucoid Pseudomonas aeruginosa. C. Aspergillus fumigatus. D. Staphylococcus aureus. E. Methicillin-resistant Staphylococcus aureus. F. Stenotrophomas maltophilia. G. Achromobacter xylosoxidans. H. Atypical mycobacterium. I. Klebsiella pneumoniae. J. Haemophilus influenzae. K. Streptococcus pneumoniae. L. Escherichia coli. Burkholderia cepacia complex is not presented as few subjects developed this infection and results were limited in interpretation.