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Published ahead of print on June 26, 2003, doi:10.1164/rccm.200211-1302OC
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American Journal of Respiratory and Critical Care Medicine Vol 168. pp. 594-600, (2003)
© 2003 American Thoracic Society

Original Article

Nasal Airway Ion Transport and Lung Function in Young People with Cystic Fibrosis

Helen L. Wallace, Pierre M. Barker and Kevin W. Southern

Institute of Child Health, University of Liverpool, Liverpool, United Kingdom; and Division of Pediatric Pulmonology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

Correspondence and requests for reprints should be addressed to Helen L. Wallace, M.D., Institute of Child Health, Alder Hey Children's Hospital, Eaton Road, Liverpool L12 2AP UK. E-mail: hwallace{at}liv.ac.uk


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
There is strong evidence that abnormal airway ion transport is the primary defect that initiates the pathophysiology of lung disease in cystic fibrosis (CF). To examine the relationship between airway ion transport abnormality and severity of lung disease, we measured nasal potential difference in 51 young people with CF using a validated modified technique. There was no correlation between any component of the ion transport measurement and clinical condition (respiratory function, chest radiograph score, or Shwachman clinical score). Thirty subjects, homozygous for the {Delta}F508 mutation, were divided into those above and those below average respiratory function for their age. There was no significant difference in any of the ion transport parameters between those with above and below average pulmonary function. Of the 51 subjects, 10 had significant hyperpolarization after perfusion with a zero Cl- solution (> 5 mV). This Cl- secretory capacity did not correlate with above average lung function. These data do not support the assertion that the extent of lung disease in CF reflects the degree of ion transport abnormality. We suggest that although an ion transport abnormality initiates lung disease, other factors (e.g., environmental and genetic modifiers) are more influential in determining disease severity.

Key Words: nasal potential difference • FEV1 • {Delta}F508 • chloride secretion

Cystic fibrosis (CF) is caused by mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene and is characterized by profound abnormality of Na+ and Cl- transport across epithelia (1). CFTR normally functions as a cAMP-regulated chloride channel and influences other ion channels, most notably by downregulating the epithelial sodium channel (2–4). In CF airways, epithelial sodium channel–mediated sodium ion absorption is increased and cAMP-mediated Cl- secretion diminished or absent. Extensive animal model and tissue culture studies have established a clear link between these airway ion transport abnormalities and the pathophysiology of CF lung disease (5). Dehydration of airway surface liquid, together with abnormal mucus production and decreased mucociliary clearance, exposes the airway to bacterial infection (6, 7). The subsequent cycle of chronic infection and extensive inflammation is well described (8).

Over 1,000 mutations of the CFTR gene have been identified and this accounts, to some degree, for the variation in phenotype severity that characterizes CF (9). For example, certain mutations with residual CFTR function are associated with preservation of pancreatic function and delayed onset of clinical symptoms (10). However, the relationship between genotype, ion transport, and pulmonary disease is less conclusive (11). Wide intragenotype variation in the severity of pulmonary disease may reflect environmental factors, the presence of polymorphisms, or non-CFTR genetic modifiers (12, 13).

A number of studies have examined the influence of airway ion transport, as determined by nasal potential difference (PD) measurement, on the severity of lung disease. One group measured baseline PD in 95 adults and determined that the 10 patients with the lowest PDs had significantly better respiratory function irrespective of genotype (14). Other groups have not been able to reproduce these findings but have suggested some correlation between severity of lung disease and cAMP-mediated Cl- secretion (15, 16). A more robust examination of the influence of Cl- secretion on respiratory function was performed in a study of twin and sibling pairs, homozygous for {Delta}F508, the commonest CFTR mutation (17). Pairs with mild respiratory disease were shown to have limited evidence of Cl- secretion, in contrast to pairs with severe disease. Another group examined five patients with the rare A455E mutation (associated with a mild respiratory phenotype) and did not demonstrate any difference in nasal PD parameters compared with five patients with a severe genotype ({Delta}F508/{Delta}F508) (18).

The relationship between the extent of airway ion transport abnormality and the severity of lung disease is important because novel therapies are being directed toward correction, either by pharmacologic or molecular means, of the CF ion transport defect. In addition, clinical trials have employed nasal PD as a surrogate outcome measure on the assumption that normalizing the CF ion transport profile would improve long-term lung function. We examined prospectively the correlation between airway ion transport abnormality, as determined by nasal PD, and respiratory condition in young people with CF.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
A definitive diagnosis of CF confirmed by raised sweat electrolytes (Cl- level > 60 mmol L-1) and/or identification of two disease–associated CFTR mutations was required for inclusion. Exclusion criteria included nasal polyposis, topical steroids, and acute rhinitis. Clinical assessment and nasal PD studies were undertaken at a point of stability (no respiratory symptoms (cough or wheeze) other than those normally experienced and no extra antibiotics).

The Liverpool Health Authority Research Ethics Committee approved the study.

Clinical Assessment
Respiratory involvement was assessed by lung function testing using a standard spirometer (Compact 2; Vitalograph Ltd, Bucks, UK) and chest radiograph (CXR). FEV1 (L) was expressed as percent predicted for age, sex, and height (19). A CXR score was allocated by a single experienced radiologist, independent of the CF team (20). An overall clinical score (Shwachman and coworkers (21)) was determined by the CF team.

Nasal PD Measurement
Nasal PD was measured under the inferior turbinate by a previously described method, designed to facilitate measurements in young people (22). The integrity of a reference electrode (silver/silver chloride disc), placed on the right forearm over an area of gently abraded skin was verified by measuring skin PD (a magnitude of PD > 30 mV was considered acceptable) (23).

The following nasal PD parameters were recorded: (1) Stable maximal baseline PD (stable max PD; reflecting epithelial Na channel–mediated Na+absorption); (2) the reduction in (1) after perfusion with 10-4 M amiloride ({Delta}amil); (3) The subsequent change in PD after perfusion with a zero Cl- solution (Cl- replaced by gluconate) with 10-5 M isoprenaline and 10-4 M amiloride ({Delta}zeroCl-/iso; reflecting cAMP-mediated Cl- secretion); (4) the response of the PD to perfusion with {Delta}zeroCl-/iso and 10-4 M ATP (adenosine triphosphate) ({Delta}ATP; Ca2+-mediated Cl- secretion).

At maximal baseline PD and following solution change, readings were taken from a point of stability (20 seconds).

Data Analysis
A sample size of 47 provides 80% power to detect a significant correlation coefficient of 0.4 (two-sided Fisher's z test). A correlation coefficient of 0.4 was considered the minimum acceptable to demonstrate a clinically relevant relationship.

Three analyses were predetermined: (1) scatter plots were constructed to assess correlation between clinical measures and nasal PD parameters. Any relationships were examined with multiple regression analysis to construct a model to account for confounding variables (age, sex, genotype); (2) in order to account for natural decline in FEV1, patients homozygous for {Delta}F508 were divided into two groups (above or below average FEV1 for age, taken from the European Epidemiological Registry of Cystic Fibrosis (24, 25), 6 to 12 years, average FEV1% predicted, 79.1 and 13–17 years, 67.8%). PD values for the above average group were then compared with the below average group (Student's t test); and (3) patients were divided according to their response to zero Cl- perfusion ("high secretors," magnitude of {Delta}zeroCl-/iso hyperpolarization > 5 mV; "low secretors" < 5 mV).

Values obtained for the CF group were compared with a non-CF group. Normality of the data distribution was assessed using the Shapiro–Wilk test and by examining histograms; the Student's t test or the Mann–Whitney U test was employed accordingly.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Subjects
Nasal PD was measured in 51 young people with CF (34 males and 17 females, mean age 13.7 years, range 5.9–17.7; Table 1) . Thirty were homozygous for {Delta}F508 and 14 were compound heterozygous for {Delta}F508 and another recognized severe mutation. One was homozygous for G551D, and two were compound heterozygous for mutations associated with severe disease. Three patients (20, 21, 39) had Class IV or V mutations associated with a mild disease phenotype. One patient (pancreatic sufficient) had only one recognized mutation (G551D). Twelve young people without CF were also studied (five males and seven females, mean age 13.7 years, range 9.1–17.7).


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  		TABLE 1. Clinical details and nasal potential difference results from all subjects

 
Clinical Condition
In the 51 subjects with CF, good correlation was demonstrated between each clinical parameter; FEV1, CXR score and Shwachman score (Figure 1 ; Pearson correlation, p < 0.01), i.e., patients with better lung function had lower CXR scores and higher Shwachman scores. Overall, the cohort had a wide range of lung function values (FEV1, 27–120% predicted, Table 1).



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  		Figure 1. Scatter plots demonstrating the relationship between FEV1, chest radiograph (CXR) score, and Shwachman score (positive correlation between FEV1 and Shwachman score [r = 0.72, p < 0.01 Pearson correlation] and a negative correlation between FEV1 and CXR [r = -0.52, p < 0.01] and Shwachman score and CXR [r = -0.65 and p < 0.01]).

 
Comparison between First Nostril Values and the Average of Both Nostrils
Nasal PD measurements were well tolerated by all subjects. In 15 cases in the CF group, only one nostril was recorded to reduce the time of the procedure in patients who were unsettled. In the 36 patients who had both nostrils recorded, we compared the average of two nostril values to the first nostril value. Mean (±SEM) values for stable max PD were -44.7 ± 2.36 for both nostrils and -49.4 ± 2.8 for the first nostril. Values for {Delta}zeroCl- were -1.4 ± 0.89 and -1.1 ± 1.14. Bland–Altman plots (26) showed wide limits of agreement for stable max PD (-27.2–17.7) demonstrating the inherent variability of basal PD, and good limits of agreement for {Delta}zeroCl- (-7.1–6.4; Figure 2) . There was no evidence of bias toward either method.



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  		Figure 2. Bland–Altman plot demonstrating the agreement between two methods of analyzing the nasal potential difference (PD) measurement in 36 children. Method a was an average of both nostrils. Method b was the value from the first nostril recording. The zero bias (continuous line), the actual mean bias (center dotted line), and the 95% limits of agreement are shown.

 
Correlation between Nasal PD Results and Clinical Parameters in CF Patients
There was no correlation between stable max PD and any of the clinical parameters as shown in Figure 3 (FEV1, r = 0.18, p = 0.2; CXR score, r = -2.7, p = 0.06; Shwachman score, r = 0.2, p = 0.16; Pearson correlation). Similarly, {Delta}amil did not correlate with FEV1 (r = -1.4, p = 0.32), CXR score (r = 0.2, p = 0.17), or Shwachman score (r = -2.2, p = 0.13). There was no correlation between {Delta}zeroCl-/iso and any of the clinical parameters (CXR, r = 0.03, p = 0.85; FEV1, r = -0.12, p = 0.4; Shwachman score r = 0.02, p = 0.87; Spearman's {rho}). There was no correlation between {Delta}ATP and clinical condition (CXR, r = 0.07, p = 0.65; Shwachman score r = -0.06, p = 0.68; Pearson correlation).



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  		Figure 3. Scatter plots demonstrating the lack of relationship between nasal PD (stable max PD and {Delta}zeroCl-/iso) and FEV1.

 
Relationship between FEV1 and Nasal PD in {Delta}F508 Patients
Thirty patients, homozygous for {Delta}F508, were divided into two groups according to their FEV1 (above average, n = 16, Table 2) . There were no differences between the two groups for stable max PD (p = 0.73), {Delta}amil (p = 0.56) or {Delta}zeroCl-/iso (p = 0.78 Mann–Whitney U test) (Figure 4) .


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  		TABLE 2. Nasal potential difference values (mean ± sem) for patients homozygous for {Delta}F508 (patients scoring above average (or equal to) fev1 for their age and patients scoring below average for their age)

 


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  		Figure 4. Stable max PD and {Delta}zeroCl-/iso for patients scoring above (or equal to), and below average FEV1 for their age group. All subjects were homozygous for {Delta}F508 (n = 30). Horizontal lines show mean values.

 
Effect of Genotype on Nasal PD
Three patients had CFTR mutations associated with a mild phenotype (two were pancreatic sufficient). All three patients had stable max PD magnitude below 40 mV but no evidence of hyperpolarization after perfusion with zero Cl- solution.

"Chloride Secretors"
Ten patients had {Delta}zeroCl-/iso hyperpolarization greater than 5 mV. Five were homozygous for {Delta}F508 and five were compound heterozygous for mutations associated with severe disease. There was no difference in clinical condition between these 10 subjects and those with {Delta}zeroCl-/iso hyperpolarization less than 5 mV (t test: FEV1, p = 0.69, CXR score, p = 0.95; Shwachman score, p = 0.8, Figure 5) . Recordings from the left nostril of Patient 26 ({Delta}F508/G551D; sweat Cl-, 103) are shown in Figure 6 . These recordings, two months apart, demonstrate the repeatability of this finding.



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  		Figure 5. Respiratory function (FEV1) in patients with a hyperpolarization response to perfusion with a zero Cl- solution and isoprenaline ({Delta}zeroCl-/iso) of more than 5 mV (high Cl- secretors) compared with less than 5 mV (low Cl- secretors).

 


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  		Figure 6. Two recordings from the left nostril of the same patient (26) taken 2 months apart which demonstrate characteristic high stable maximal baseline PD. The large hyperpolarization after change to a zero Cl-/iso solution is not characteristic of CF (tracing B; arrow during zero Cl-/iso response indicates movement).

 
Comparison of PD Results in CF and Non-CF Subjects
Nasal PD results for young people with and without CF are shown in Table 3 . Stable max PD and {Delta}amil were significantly higher in the subjects with CF (stable max PD, p < 0.0001 t test; {Delta}amil, p < 0.0001, t test,). Young people without CF had a greater hyperpolarization of PD after perfusion with zero Cl- solution ({Delta}zeroCl-/iso, p < 0.0001, Mann–Whitney U test). However, subjects with CF had a greater hyperpolarization after perfusion with ATP ({Delta}ATP, p < 0.03, t test).


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  		TABLE 3. Nasal potential difference values (mean ± sem) for cystic fibrosis and noncystic fibrosis group

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The extent to which airway ion transport abnormalities influence the degree of lung disease in CF is an important issue because measurement of airway ion transport is widely used as a surrogate endpoint for clinical trials. Ion transport across nasal epithelia shares characteristics with more distal airways (27). Measurement of nasal PD has been used as a surrogate for more distal ion transport processes, and recent studies demonstrating distinct nasal PD profiles in adults susceptible to high altitude pulmonary edema suggest that this is valid (28).

The ion transport abnormalities in CF initiate an environment that exposes the lung to repeated infection and inflammation. What remains unclear is whether the severity of lung disease is a result of the extent of ion transport abnormality and, if so, which component of ion transport is most influential. For example, is sodium ion hyperabsorption more important than lack of cAMP-mediated Cl- secretion, or are both critical to the initiation and/or development of CF lung disease.

This study examined the individual contribution of these ion transport processes to CF lung disease by prospectively examining the nasal PD profile of young people with CF. We did not demonstrate any significant relationship between ion transport and lung function. There was no relationship between the extent of sodium ion hyperabsorption (as determined by the stable maximal baseline PD and response to perfusion with amiloride) and FEV1. Chloride secretory capacity (as determined by the PD response to perfusion of a zero Cl- solution with isoprenaline) did not correlate with FEV1. An overall evaluation of subjects including all genotypes, showed no correlation between ion transport and clinical condition. In addition, patients with evidence of relatively high Cl- secretion ({Delta}zeroCl-/iso hyperpolarization > 5 mV) did not demonstrate better respiratory condition than low Cl- secretors.

The strengths of this study include the number of patients recruited and the wide range of clinical conditions in this cohort. In addition, the clinical parameters were assessed rigorously in an unbiased manner at a time of clinical stability. The finding of close correlation between these clinical parameters suggests that they are a true reflection of the clinical condition of the patients. A wide range of respiratory phenotype was demonstrated in this cohort increasing the power of the study to detect a significant correlation. Limitations of this study include the cross-sectional nature, the fact that only one nostril was measured in some patients and the natural decline in FEV1 that occurs in this age group. Patients who we have measured on more than one occasion show good repeatability (see Figure 6). Some of the younger patients had only one nostril recorded to reduce the measurement time. Although this would increase the variability of the test procedure, a separate analysis comparing first nostril values to the average of both nostrils showed no difference in the outcome of the study using either method. The decline in lung function with age was taken into account in the analysis by using average FEV1 values for age.

Previous studies have examined the relationship of nasal PD and lung disease (14, 15). Significant relationships have been reported; however, the clinical differences between groups are small. Thomas and coworkers report a correlation between FEV1 and {Delta}zeroCl-/iso in men, but not women, homozygous for {Delta}F508 (16). Although men and women had the same range of {Delta}zeroCl-/iso, they suggest that this may account for the reported better prognosis of CF men. The extent of Cl- secretion identified was small (only one patient > 5 mV). In our prospective study, the 10 patients with Cl- secretion more than 5 mV did not have better respiratory condition than subjects with lower Cl- secretion.

The finding of a chloride secretory capacity in patients with "severe" genotypes is consistent with previous nasal PD studies. Ho and coworkers identified a small number of "chloride secretors", at least one of whom was homozygous for {Delta}F508 (15). Walker and coworkers did not demonstrate any ion transport differences between patients homozygous for {Delta}F508 and patients with A553E, a mutation associated with mild disease (18). In vitro studies suggest that A553E is associated with residual CFTR activity; however, this Cl- conductance was not evident from the in vivo nasal PD studies.

Data from the European study of {Delta}F508 sibling pairs (17) and others (15, 16) suggest that patients, homozygous for a severe mutation, can have Cl- secretory capacity, as determined by nasal PD measurement. This Cl- secretion may reflect "modifier" genes, possibly coding for alternative channels or for proteins that assist trafficking of mutant CFTR to the cell membrane. The European {Delta}F508 study reports that such Cl- secretory capacity may be associated with better clinical condition ("mild" patients: mean {Delta}Cl--free PD response, -5.7 ± 6.0; "severe" patients -0.7± 2.2 mV, p = 0.05). In our study, there was no evidence of better respiratory function in the 10 patients with {Delta}zeroCl-/iso hyperpolarization more than 5 mV.

This study was designed to examine the hypothesis, "Young people with severe CF lung disease have a more pronounced airway ion transport abnormality." Our data do not support this hypothesis. However, this study was underpowered to examine the ion transport characteristics of patients with mutations associated with a mild respiratory phenotype. Three such patients were included (although one had severe respiratory involvement). All had relatively low stable max PDs but no evidence of Cl- secretory capacity. A recent study found abnormal but varied nasal PD values in a small number of children with mutations associated with mild respiratory phenotype and intermediate sweat chloride levels (29). More work is needed in this area.

Other factors may influence the degree of respiratory involvement in patients with CF. A number of studies have demonstrated association between certain genetic variants and respiratory function in CF. In particular, polymorphisms affecting the function of genes that mediate innate immunity and other inflammatory processes have been highlighted (30–33). It is feasible that although the CF ion transport defect is the initiating step in CF lung pathology other factors may subsequently have more influence on the severity of lung involvement.

To summarize, we examined a large cohort of young people with CF with a wide spectrum of lung disease. We did not detect any relationship between the extent of lung disease and the extent of airway ion transport abnormality as determined by nasal PD measurement. These findings are consistent with the views of other groups who suggest a "point of no return" when referring to the development of lung disease in CF (34). Although airway ion transport plays a key role in establishing an environment for lung disease in CF, it seems likely that other factors have more influence on the extent of that involvement.


   Acknowledgments
 
The authors would like to thank the young people who helped with this study, Dan Gillie for technical advice, Dr. Gill Lancaster for statistical advice, and Dr. Ken Friedman for information regarding genotype analysis.


   FOOTNOTES
 
Supported by grants and fellowships (H.L.W.) from the United Kingdom Cystic Fibrosis Trust and the Medical Research Council.

Received in original form November 8, 2002; accepted in final form June 25, 2003


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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I Fajac, D Hubert, D Guillemot, I Honore, T Bienvenu, F Volter, J Dall'Ava-Santucci, and D J Dusser
Nasal airway ion transport is linked to the cystic fibrosis phenotype in adult patients
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Establishing a diagnosis of cystic fibrosis
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