Mutations that permit residual CFTR function delay acquisition of multiple respiratory pathogens in CF patients
© The Author(s) 2010
Received: 19 July 2010
Accepted: 8 October 2010
Published: 8 October 2010
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.
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.
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).
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.
Cystic fibrosis (CF) is the most common autosomal recessive life-shortening disorder in the Caucasian population and progressive obstructive lung disease is the primary cause of mortality[1, 2]. Persistent respiratory infection by particular organisms, such as Pseudomonas aeruginosa (Pa) and Burkholderia cepacia complex (Bcc), are hallmarks of CF lung disease and lead to the progressive obstructive lung disease[2–5]. Infection with Pa is often preceded by infection with other organisms that are rarely cultured from healthy individuals such as Staphylococcus aureus. Additionally, a number of other pathogens such as methicillin resistant Staphylococcus aureus (MRSA), Achromobacter xylosoxidans (Ax) and Aspergillus fumigatus (Asp) have been found to infect CF patients and affect the severity of lung disease in these patients. Mutations which permit residual CFTR function and confer a "mild" phenotypic effect have been associated with lower rates of Pa infection[9, 10]. However, it is not clear whether residual CFTR function also influences acquisition of respiratory pathogens other than Pa .
Teasing out the role that CFTR genotype has on CF lung infection is important for several reasons. Recent success in the identification of small molecules augmenting CFTR function raises the possibility that delay of infection might be used as a measure for clinical efficacy of these new treatments, especially in children where few alternative options exist. Secondly, patient populations have been accrued to find genetic modifiers of traits such as risk of infection and quantifying the contribution CFTR has to infection aids the search for genetic modifiers of this trait providing novel therapeutic targets for CF. Finally, 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. If this is the case in humans, then alteration in CFTR function should correlate with infection with a variety of respiratory pathogens. To address these issues, we evaluated the correlation between CFTR genotype and infection with a variety of pathogens using detailed infection data collected by the U.S. CF Twin and Sibling Study (CFTSS).
All subjects in the U.S. CFTSS were recruited on the basis of having a twin or sibling affected with CF. All enrolled patients met CF diagnostic criteria and 99% attend CF care centers in the United States. Isolation of patient DNA, identification of CFTR mutations, and zygosity testing have been previously described[14, 16]. Written, informed consent/assent was obtained from all subjects and/or their guardians, and this study was approved by the Johns Hopkins University Institutional Review Board.
Definitions of infection
Thirteen organisms were studied including Pseudomonas aeruginosa (Pa), mucoid Pa (MPa), Staphylococcus aureus (Sa), Methicillin resistant Sa (MRSa), Burkholderia cepacia complex (Bcc), Atypical mycobacteria (atyp), Aspergillus fumigatus (Asp), Stenotrophomonas maltophilia (Sm), Achromobacter xylosoxidans (Ax), Haemophilus influenzae (Hi), Streptococcus pneumoniae (Sp), Escherichia coli (Ec), and Klebsiella pneumoniae (Kp). Subjects were defined as having an "infection" with the organism in question if they had a positive oropharyngeal culture (throat, sputum, or bronchoalveolar lavage culture) for that particular organism (FirstInfx), regardless of whether the subject was positive for other organisms. An additional inclusion criterion was that a negative culture for the organism had to have been obtained a minimum of one week prior to the first positive culture to insure that subjects were in follow-up and routine cultures were being obtained. Patients treated at CF care centers in the U.S. have complete microbiological assessment of respiratory cultures at least annually and preferably quarterly. All subjects were passively followed-up after enrollment in the CFTSS until December 31, 2008 with culture data provided from their care centers and the CF Foundation Patient registry. Subjects were excluded if a respiratory culture was never performed prior to December 31, 2008.
A separate analysis of infection with Pa, MPa and Asp was performed using 3 additional criteria to define infection: 1) chronic infection (ChronInfx): 3 positive cultures within 6 months with each culture separated by at least 1 month (similar to that employed in Europe) 2) multiple infection (MultiInfx): at least 3 positive cultures, but not meeting the definition for ChronInfx (as most patients in the U.S. do not attend CF clinic 3 times in 6 months); and 3) persistently infected (PersInfx): multiple cultures obtained in 3 consecutive years with positive cultures observed in at least 2 of the 3 years (recently used in a CF modifier study).
CFTR genotypes and other variables
Classification of CFTR alleles
Defective Protein Synthesis (nonsense, frameshift, aberrant splicing)
1078delT, 1154 insTC, 1525-2A > G, 1717-1G > A, 1898+1G > A, 2184delA, 2184 insA, 3007delG, 3120+1G > A, 3659delC, 3876delA, 3905insT, 394delTT, 4010del4, 4016insT, 4326delTC, 4374+1G > T, 441delA, 556delA, 621+1G > T, 621-1G > T, 711+1G > T, 875+1G > C, E1104X, E585X, E60X, E822X, G542X, G551D/R553X, Q493X, Q552X, Q814X, R1066C, R1162X, R553X, V520F, W1282X, Y1092X
Abnormal Processing and Trafficking
A559T, D979A, ΔF508, ΔI507, G480C, G85E, N1303K, S549I, S549N, S549R
Defective Channel Regulation/Gating
G1244E, G1349D, G551D, G551S, G85E, H199R, I1072T, I48T, L1077P, R560T, S1255P, S549(R75Q)
Decreased Channel Conductance
A800G, D1152H, D1154G, D614G, delM1140, E822K, G314E, G576A, G622D, G85E, H620Q, I1139V, I1234V, L1335P, M1137V, P67L, R117C, R117P, R117H, R334W, R347H, R347P, R347P/R347H, R792G, S1251N, V232D
Reduced Synthesis and/or Trafficking
2789+5G > A, 3120G > A, 3272-26A > G, 3849+10kbC > T, 5T variant, 621+3A > G, 711+3A > G, A445E, A455E, IVS8 poly T, P574H
Statistical analysis and regression modeling
Time to acquisition of the first positive culture for an organism was assessed by the Kaplan Meier product limit estimator and the log-rank test. Cox proportional hazard regression models were used to account for covariates which could affect the relationship of CFTR genotype and age of acquisition for a particular organism. Covariates were identified a priori based on clinical experience and review of literature. Univariate regression was first performed with co-variates of gender (male vs. female), ethnicity (Caucasian vs. non-Caucasian), pancreatic status (pancreatic insufficient vs. pancreatic sufficient), FEV1BeforeInfx (linear co-variate), and cultures per year (linear co-variate) to identify significant co-variates. Co-variates with a p-value < 0.05 (pancreatic status, FEV1BeforeInfx, and cultures per year) were included in a multivariate Cox regression. In this regression, only FEV1BeforeInfx and cultures per year remained significant with p-values < 0.05. The final multivariate Cox regression model included FEV1BeforeInfx for the organism and cultures per year.
A second analysis was performed also using Cox regression to assess the relationship of CFTR with alternative ways of defining infection status for Pa, MPa and Asp. This regression was also adjusted for FEV1BeforeInfx for the organism and cultures per year. The time to "event" was defined as the age of the subject from birth until the first positive culture that would be included to meet the infection definition. In other words, for a subject meeting the definition of ChronInfx, the subject would need 3 positive cultures within 6 months but each 1 month from the other and the age of the subject at the first of the 3 positive cultures would be used. If subjects did not meet the definition of infection the age at the last obtained culture is used for censoring. All statistical calculations were performed using Intercooled Stata 10 (Stata Corp., College Station, TX).
Clinical characteristics and infection rates in the study population
Overall prevalence of organisms in the U.S. CF Twin and Sibling Study, prevalence of infections in the U.S. CF Twin and Sibling Study in 2008 and the U.S. CF Foundation Registry in 2008.
U.S. CF Twin and Sibling Study Overall
U.S. CF Twin and Sibling Study 2008
CF Foundation Registry 2008
Characteristics of study subjects
Age (yrs) last visit ± SD (range), (n)
15.82 ± 8.60 (0.44-57.31) (1209)
18.59 ± 12.87 (0.54-63.94) (159)
Maximal FEV 1 CF% since last clinic visit, (n)
0.68 ± 0.26 (1111)
0.75 ± 0.25 (145)
Average number of cultures per subject per year ± SD, (n)
3.89 ± 1.92 (1201)
3.93 ± 2.27 (159)
Residual CFTR function decreases the risk of respiratory infection by multiple organisms
As noted in TABLE 2, subjects with 'Residual' CFTR function and those with 'Minimal' CFTR function differ in a number of respects, therefore a Cox proportional hazards model was created that incorporated these difference as covariates. The final multivariate Cox regression included lung function (FEV1BeforeInfx) and cultures per year. Nine of the 13 organisms were found to have a significant hazard ratio (HR) indicating an increased risk of acquisition in subjects with 'Minimal' CFTR function (FIGURE 1). For Pa, the hazard ratio was increased 3 fold for those with 'Minimal' function when compared to those with 'Residual' function. Increased risk for the other 8 organisms ranged from 1.7 to 3.8. Bcc is not presented in the figure as it was found to not be associated with CFTR genotype by log rank or Cox regression.
Residual CFTR function decreases risk of infection with Pa, MPa and Asp regardless of infection definition
Risk of infection is increased for 'Minimal' CFTR function using any definition of infection with Pseudomonas aeruginos a, mucoid Pseudomonas aeruginosa and Aspergillus fumigatus.
(n included in analysis)
(% of class positive)
(% of class positive)
Adjusted Hazards Ratioa
3.17 (2.10, 4.78)
5.47 (2.20, 13.58)
3.81 (2.32, 6.28)
3.32 (2.00, 5.50)
FirstInfx M Pa
2.93 (2.09, 4.09)
ChronInfx M Pa
3.85 (2.00, 7.39)
MultiInfx M Pa
3.11 (2.09, 4.62)
PersInfx M Pa
3.14 (2.06, 4.76)
3.77 (2.24, 6.35)
18.97 (3.73, 96.43)
3.22 (1.73, 5.98)
4.83 (2.47, 9.46)
Multivariate Cox regression was used to assess the relationship of CFTR genotype with acquisition of infection using each of these different definitions as the primary outcome. Subjects with 'Minimal' CFTR function had a substantially higher risk of acquiring Pa, MPa and Asp than those with 'Residual' CFTR function for any definitions used (TABLE 4). Thus, use of an alternate definition of infection does not substantially alter the association between predicted CFTR function and acquisition of Pa, MPa or Asp.
CFTR associated risk of infection is influenced by lung function status at the time of acquisition
Lung strataa specific hazard ratios for the association of presence of an infection with class mutation status
Lung Function <0.50c
Lung Function 0.50-0.75c
Lung Function 0.75-0.9c
Lung Function >0.9c
3.17 (2.10, 4.78)
1.59 (0.78, 3.24) (n = 81)
3.74 (1.70, 8.22) (n = 112)
4.17 (1.45, 12.0) (n = 110)
4.01 (1.92, 8.36) (n = 133)
2.93 (2.09, 4.09)
1.59 (0.78, 3.22) (n = 192)
3.80 (2.07, 6.98) (n = 227)
4.23 (2.01, 8.92) (n = 246)
3.83 (2.06, 7.11) (n = 255)
3.78 (2.24, 6.37)
2.85 (0.77, 10.63) (n = 250)
10.22 (3.25, 32.21) (n = 282)
4.51 (1.46, 13.92) (n = 269)
2.82 (1.34, 5.93) (n = 289)
1.70 (1.13, 2.53)
3.41 (1.43, 8.16) (n = 74)
1.05 (0.54, 2.03) (n = 83)
0.90 (0.40, 2.06) (n = 66)
1.94 (1.02, 3.70) (n = 64)
2.27 (1.37, 3.75)
2.04 (0.71, 5.87) (n = 237)
2.06 (0.84, 5.05) (n = 262)
1.80 (0.76, 4.30) (n = 260)
3.40 (1.41, 8.21) (n = 273)
2.33 (1.06, 5.12)
2.12 (0.27, 16.66) (n = 265)
5.41 (0.42, 70.41) (n = 294)
1.40 (0.52, 3.78) (n = 292)
2.47 (1.06, 5.72) (n = 303)
3.27 (1.95, 5.47)
2.70 (0.88, 8.31) (n = 229)
3.62 (1.52, 8.62) (n = 257)
2.45 (1.12, 5.33) (n = 260)
3.64 (1.31, 10.13) (n = 247)
2.57 (1.25, 5.26)
1.94 (0.42, 9.05) (n = 252)
8.41 (1.83, 38.58) (n = 282)
2.07 (0.59, 7.30) (n = 275)
1.93 (0.64, 5.82) (n = 293)
3.47 (1.27, 9.48)
0.28 (0.07, 1.06) (n = 233)
7.87 e15 (2.30 e15, 2.69 e16) (n = 250)
7.55 e15 (2.60 e15, 2.19 e16) (n = 247)
4.73 (1.15, 19.43) (n = 258)
Pulmonary disease in CF is complicated by patients acquiring numerous different organisms at different periods of time during his/her lifetime. These organisms tend to progress from Sa and Hi to Pa. While Pa has been extensively studied for its relationship with CFTR mutations, the underlying defect of CF, few studies have evaluated the effect that CFTR genotype has on infection risk for other organisms commonly cultured from CF respiratory tracts. Our study corroborates the finding that CFTR mutations which permit 'Residual" CFTR function (i.e. class IV or V mutations) are associated with reduced rates and delayed acquisition of Pa infection[10, 11]. We substantially extend this observation to include numerous other organisms commonly cultured from CF patients (mucoid Pa, Staphylococcus aureus, MRSA, Aspergillus fumigatus, Stenotrophomonas maltophilia, Achromobacter xylosoxidans, atypical mycobacterium and Klebsiella pneumoniae) indicating that CFTR dysfunction appears to cause a global alteration in infection resistance in humans. This concept is consistent with recent studies which indicate loss of CFTR function causes a pervasive defect in resistance to respiratory infection in pig models of CF. Additionally this study shows that the concept of "mild" CFTR mutations (often 'Residual' function mutations) versus "severe" CFTR mutations (often 'Minimal' function mutations) may extend beyond pancreatic status to other features such as lung infection. Furthermore, we show that the association between CFTR genotype and respiratory infection has a complex relationship with the severity of lung disease. CFTR mutations that permit 'Residual' function reduce the risk of infection with multiple organisms in patients with mild lung dysfunction evidenced by near normal forced expiratory volumes. However, in patients with compromised lung function, the protective effect of 'Residual' CFTR function is lost for most of the organisms studied.
To date, studies on the role of CFTR as a risk factor for acquisition of infectious organisms have concentrated on the most common mutation, F508del. A few studies have assessed the role of the CFTR genotype beyond the classification of F508del homozygotes versus all others. One study found that mis-sense and splice mutations predicted to confer "mild" effect were associated with lower rates and later acquisition of Pa infection. However, mis-sense and splice-site mutations have different effects upon CFTR function; the former being associated with protein formation (and possible residual function) while the latter is usually associated with no protein being made (and no residual function). Two subsequent studies[10, 11] demonstrated that stratifying CFTR mutations by putative function was associated with lower rates of Pa infection. One of these studies attempted to associate CFTR mutation class with infection risk for other organisms but failed to show a reliable association. One reason this current study found an association of CFTR genotype with multiple respiratory pathogens may be due to the increased power afforded by a larger sample size when subjects with class IV or V mutations are combined (as opposed to assessing each mutation class separately). Alternatively, non-genetic factors may play a role as the prior study was performed in Europe as opposed to the current U.S. study.
Furthermore, the role of CFTR in the acquisition of lung infection has been debated. One possibility is that CFTR on epithelial cell membranes binds organisms directly by recognizing the lipopolysaccharide coat of Pa  thus allowing endocytosis and eventual destruction of Pa. Loss of this bacterial clearance process due to mutations that do not permit residual CFTR function (class I, II or III) is postulated to underlie the chronic infectious state associated with Pa. This however does not fully explain the relationship observed for CFTR and other organisms. A second hypothesis posits that defective clearance of infecting organisms due to altered properties of airway surface liquid and innate defense caused by CFTR dysfunction [27, 28]. In this scenario, our results might suggest that mutations causing a moderate loss of CF function lead to less severe changes in epithelial barriers to infection and consequently lower rate of infection with a number of organisms commonly found in the CF lung. Regardless of mechanism, the findings of this study indicate that reduced CFTR function leads to a global disruption of infection control and acquisition.
We have to acknowledge that there are several weaknesses in this study. First, the study was retrospective and patients were enrolled on the basis of being diagnosed with CF and having a sibling diagnosed with CF. This inclusion criterion may have skewed our population as survival of both siblings until entry in our study was required. To assess for a possible bias toward milder CF patients who may have a lower rate of respiratory infection, we compared our data to the general U.S. CF population in the CFF registry and found rates of infection in this study to be similar to the unrelated U.S. CF population (TABLE 2). Another weakness is that we did not apply a correction for age of diagnosis of CF as this event may have been precipitated by a positive respiratory culture. To address this shortcoming, we ensured that subjects had at least one negative respiratory culture for the organism being studied prior to entry into the analysis thereby excluding individuals who were infected at the time of CF diagnosis.
Strengths of this study include sample size, the conservative use of alternative definitions of infection and assessment of lung function prior to the acquisition of the organism. Using a mean survival time of 5 years for the control group ('Minimal' function), 5 years for accrual of all subjects, 10 years of follow-up time and 80% power, we had an adequate sample size to detect a hazard ratio (HR) of 1.3. As shown in FIGURE 1, organisms that demonstrated a significant correlation with CFTR function had HRs that considerably exceeded this threshold. While our main outcome measure was the initial acquisition of an organism, we also stratified patients using 3 other definitions for infection. As highly similar results were obtained when using either of these definitions, we conclude that our results are independent of the criteria used to assign infection status. Inclusion of additional definitions of infection also helped overcome the issue of using a single throat culture (if that was the only culture information for a subject) to determine infection status since throat cultures are known to have poor negative predictive value. By including criteria which require assessment of multiple cultures, correct classification of subjects is more assured. Finally, by assessing lung function prior to the acquisition of the infectious organism analyzed, we were able to evaluate whether the association between predicted CFTR function and infection status was dependent on the severity of lung disease around the time of first infection.
In conclusion, genotypes predicting 'Minimal' CFTR function are associated with increased risk and earlier age of infection by multiple organisms. For those with decreased lung function, 'Residual' CFTR genotype no longer provides a protective effect on infection risk. These observations suggest that 1) adjustment for CFTR functional genotype may be necessary in genetic modifier studies of infection, 2) monitoring infection status in patients with mild lung disease, especially children, could be an outcome measure for therapies that augment CFTR function and 3) augmentation of CFTR function may not reduce the risk of infection in patients with severe lung disease.
List of Abbreviations
Burkholderia cepacia complex
cystic fibrosis transmembrane conductance regulator
U.S. CF Twin and Sibling Study
mucoid Pseudomonas aeruginosa
methicillin resistant Staphylococcus aureus
first positive culture
chronic infection: 3 positive cultures within 6 months each 1 month from the previous
multiple infection: 3 positive cultures in the subjects lifetime
persistently infected: 2 positive cultures each in a separate year within 3 consecutive years
- FEV1 :
forced expiratory volume in one second
maximum CF-specific percentile forced expiratory volume in one second in the year before the first positive culture for an organism
The authors would like to acknowledge the numerous CF patients, families, research coordinators and clinicians who participate in the CF Twin and Sibling Study. The authors would also like to thank Neeraj Sharma, DVM, PhD, and Vishal Doshi, MBBS, MPH for their thoughtful discussions; Patricia Cornwall for her administrative assistance; Sara Ritter, BA and Darci Ferrer, BS for technical expertise; Terri Beaty, PhD and Jennifer Mulle, PhD for their expert advice on epidemiology and genetic epidemiology. This work was supported by the National Institutes of Health Grants (NHLBI T32 HL072748 (D.M.G.); NIDDK DK99003 (G.R.C.); NHLBI HL068927 (G.R.C.); NIDDK DK076446 (S.M.B.)). This work was partially presented in abstract form in Pediatric Pulmonology 2008 Supplement 31: Abstract 232 and Pediatric Pulmonology 2009 Supplement 32: Abstract 170.
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