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

Deanna M Green,J Michael Collaco,Lindsay B Henderson,Kathleen M Naughton,Garry R Cutting,Scott M Blackman,Kathryn E Mcdougal,Patrick R Sosnay

doi:10.1186/1465-9921-11-140

Deanna M Green, J Michael Collaco + Show 6 more

Open Access

https://doi.org/10.1186/1465-9921-11-140

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Abstract

BackgroundLung 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.MethodsLung 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.ResultsSubjects 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).ConclusionsResidual 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.

Highlights

Lung infection by various organisms is a characteristic feature of cystic fibrosis (CF)
If this is the case in humans, alteration in CFTR function should correlate with infection with a variety of respiratory pathogens
Our study corroborates the finding that CFTR mutations which permit ‘Residual’ CFTR function are associated with reduced rates and delayed acquisition of Pseudomonas aeruginosa (Pa) infection [10,11]. We substantially extend this observation to include numerous other organisms commonly cultured from CF patients indicating that CFTR dysfunction appears to cause a global alteration in infection resistance in humans

Summary

Introduction

Lung infection by various organisms is a characteristic feature of cystic fibrosis (CF). Mutations which permit residual CFTR function and confer a “mild” phenotypic effect have been associated with lower rates of Pa infection [9,10] It is not clear whether residual CFTR function influences acquisition of respiratory pathogens other than Pa [11]. Neonatal CF pigs show acquisition of infection with a variety of organisms indicating that loss of CFTR function causes a pervasive defect in lung defense [13]. If this is the case in humans, alteration in CFTR function should correlate with infection with a variety of respiratory pathogens.

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