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Home医源资料库在线期刊美国呼吸和危急护理医学2005年第171卷第2期

Ventilation Inhomogeneities in Relation to Standard Lung Function in Patients with Cystic Fibrosis

来源:美国呼吸和危急护理医学
摘要:TimeeCEventRelationshipTheevaluationofthetime-eventrelationshipforoccurrenceofabnormallungfunctionrepresentedbyeachlungfunctionparameterisgiveninFigure3。Ventilationinhomogeneityassessedbynitrogenwashoutandventilation-perfusionmismatchbycapnographyinstableand......

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    Department of Pediatrics and Division of Human Genetics, University of Berne, Berne, Switzerland

    ABSTRACT

    Based on serial lung function measurements performed in 142 children (68 males; 74 females) with cystic fibrosis (CF), prospectively evaluated over an age range of 6 to 20 years, we attempted to determine whether the lung clearance index (LCI) as a measure of ventilation inhomogeneities could be a discriminating factor of disease progression. Annual follow-up lung function measurements featuring FRC determined by whole-body plethysmography and multibreath nitrogen washouts, effective specific airway resistance, floweCvolume curves, LCI, and gas exchange characteristics were analyzed by linear mixed-model analysis and Kaplan-Meier statistics. The earliest occurring and strongest factor of progression was the LCI, followed by maximal expiratory flow (MEF50) and FRC determined by plethysmography (p < 0.0001). Associations between onset of chronic Pseudomonas aeruginosa infection and CF transmembrane conductance regulator (CFTR) genotype with FEV1 (p = 0.027) and FVC (p = 0.007) were identified. The study shows that the LCI predicts earlier in life and represented much better functional progression than FEV1. Moreover, there is no single functional predictor of progression in CF, but aside from risk factors, such as onset of chronic P. aeruginosa infection and genotype, pulmonary hyperinflation, airway obstruction, and ventilation inhomogeneities are important pathophysiologic processes that should be evaluated concomitantly as determinants of lung progression in CF.

    Key Words: cystic fibrosis  genotype  onset of progression  Pseudomonas aeruginosa  ventilation inhomogeneities

    Chronic lung disease is the most serious clinical expression of cystic fibrosis (CF), and the majority of patients with CF die from respiratory failure due to endobronchial infection and neutrophil-dominated inflammation (1, 2). Although the pathophysiologic basis of CF has been extensively studied, the heterogeneous course of CF still requires more convincing elucidation, and much of the variability in morbidity and mortality remain unexplained by the current conceptualization of disease processes. FEV1 and several indexes of the floweCvolume curve have been shown to be good independent predictors of survival (3) and the major indicators for lung transplantation (4, 5). To our knowledge there are no studies investigating the relationship between changes of lung volumes (especially pulmonary hyperinflation and trapped gases), intrapulmonary gas distribution, and airflow limitation over time.

    Because onset and progression of lung disease are the main determinants of morbidity and mortality in CF, it is essential to define lung function parameters identifying pathophysiologic alterations of lung function as early as possible in life. Moreover, whereas some investigators were not able to find any associations between pulmonary disease and the genotype (6, 7), others, including our own group, have reported specific CFTR genotypes correlating with clinical, radiologic, or functional pulmonary status (8eC11). Finally, the age at onset of chronic Pseudomonas aeruginosa infection was also specified as a risk factor of lung disease progression (12eC15). However, to evaluate such longitudinal data and to define confounders and risk factors, advanced statistical approaches such as univariate or multivariate linear mixed-model (LMM) regression analysis are needed. Using such statistical procedures, the effects of the various parameters on average rates of change in lung function and cohort patterns can be elucidated, especially when data are obtained from individuals in irregularly spaced serial measurements (16, 17).

    The aim of the present study was to evaluate the progression of lung disease in CF based on lung function parameters as indicators of specific functional processes. Therefore, changes in lung volume, flow limitation, and ventilation distribution abnormalities were studied in a comprehensive prospectively investigated cohort of CF patients with known genotype, followed over a substantial life span of 6 to 20 years. Some of the results of this study have been previously reported in the form of an abstract (18).

    METHODS

    A detailed description of the study population and methods, including signal processing of lung function measurements, their computation, their sex-, age-, and growth-independent calculation, and their statistics, is presented in the online supplement.

    Subjects

    The current study cohort was assembled from the CF database at the University Children's Hospital of Berne, recruiting patients with CF from a population of 800,000 people of mainly Swiss and hence Central European origin. From this database annual lung function measurements of 142 children and adolescents (68 males; 74 females) fulfilled the inclusion criteria of the present study: (1) diagnosis based on the presence of characteristic phenotypic features (19), (2) confirmed by a duplicate quantitative pilocarpine iontophoresis sweat test measuring both Na and Cl values greater than 60 mEq/L, as well as by (3) the identification of the genotype using an extended mutation screening (20eC22), (4) documented onset of chronic P. aeruginosa infection (12), and (5) complete documentation with respect to case history, continuous annual follow-up of clinical findings, biometric data, and lung function data from age 6 to 20 years. With the exception of two patients, pancreatic insufficiency was present in all cases at the time of diagnosis. The patient age at onset of chronic P. aeruginosa infection was defined as the age at first recovery of P. aeruginosa in sputum culture that was followed by positive cultures 6 to 12 months thereafter (12, 23). Patients with intermittent colonization of P. aeruginosa were excluded from the study, and no patients with Burkholderia cepacia were included in the study. Ten patients died during the observation period. Five patients underwent transplantation, including one liver and four lung transplantations. The study protocols have been approved by the Departmental Ethics Committee of the Children's Hospital and by the Governmental Ethics Committee of the State of Berne, Switzerland. The medical-therapeutic regimens followed international standards of the United States, Canada, and European guidelines (24eC28). On that basis, treatment was open but individually tuned based on symptoms, history, sputum cultures, and lung function. Management consisted of physiotherapy (mainly autogenic drainage, positive expiratory pressure-mask and flutter), bronchodilator treatment (if effectiveness individually was proven), oral or intravenous antibiotics, nebulized rhDNase (if effectiveness individually was proven), supplementation of nutrients, pancreatic enzymes, and vitamins.

    Pulmonary Function Measurements

    Measures of static lung volumes, airflow during forced expiration, and intrapulmonary gas distribution were taken as indexes to assess the type and degree of dysfunction. Lung function testing was performed using conventional whole-body plethysmography and by multiple breath nitrogen washout (MBNW) (29eC31). As an independent variable of the washout curve, the lung clearance index (LCI), defined according to the equation: LCI = CEVN2(tE)/FRCMBNW was used, where CEVN2(tE) is the cumulative expired volume to reach an end-tidal N2 concentration of 2% and FRCMBNW is the concomitantly computed FRC. Multibreath washout tests provide objective information about lung ventilation during quiet breathing, and due to advanced labor technology, data acquisition, and computer analysis this technique is applied more and more in clinical routine (32eC37), especially also in preschool children (38). For the present study the specific targets were (1) the FRC determined by whole-body plethysmography (FRCpleth), (2) the lung clearance index (29, 30, 35eC37, 39eC41) as index of intrapulmonary gas distribution, (3) the indexes of flow limitation (FVC, FEV1, and MEF50 [maximal expiratory flow]), and (4) the airway patency expressed as specific effective airway resistance (42). To present individual values of lung function numerically independent from sex, age, and growth status, lung function data were expressed as SD-score (SD-S) by z transformation (43) based on sex- and height-specific regression equations for healthy subjects (30, 42, 44). The volume of trapped gas (VTG) was calculated as difference between FRCpleth and FRCMBNW, both expressed in SD-S.

    Genotype Analysis

    Genomic DNA extracted from ethylenediaminetetraacetic acid blood samples or cell material obtained by buccal-cell brushing (22) were used for the mutation screening of the entire coding sequences of the CFTR gene in each patient, allowing rapid and sensitive detection of 97eC98% of known as well as novel CF mutations, as previously described (21). Patients were classified into four genotype groups according to the frequencies of our population specific genotypes.

    Data Analysis and Statistical Evaluation

    SPSS (version 11, SPSS Inc., Chicago, IL), and Prism (version 4.0, GraphPad Software, Inc., San Diego, CA) software were used for statistical and graphic analyses. LMM analysis was used to provide reliable estimates of both individual changes over time of an outcome and presumed associated risk factors, such as genotypes or onset of chronic P. aeruginosa infection. Results with a p < 0.05 were considered statistically significant. The time at onset of abnormal lung function was calculated using Kaplan-Meier plot analysis.

    RESULTS

    Patient Population

    The baseline characteristics of the study cohort are presented in Table 1. From the 142 patients with CF, 68 males (47.8%) and 74 females (52.2%), 83 patients (58.3%) were homozygous for the F508(2) mutation, 13 patients (9.2%) were compound heterozygous for the F508 and 3905ins frameshift mutation (second most frequent in Switzerland), 12 patients (8.5%) presented as compound heterozygous for the F508 and R553X nonsense mutation, and 34 patients (23.9%) had other miscellaneous genotypes. Ten patients died during the observation period (four F508(2) homozygotes at mean age 14.2 ± 6.9 years; five 3905insT/F compound heterozygotes at mean age 14.7 ± 4.8 years; and one Q525X/F at age 18.4 years). The mean age at onset of chronic P. aeruginosa infection was 5.1 ± 4.4 years (0.1eC20.5 years) with 42 patients (29.6%) presenting early onset of chronic P. aeruginosa infection (age < 3 years) and 69 patients (48.6%) late onset of chronic P. aeruginosa infection (age > 3 years). Thirty-one patients (21.8%) were free from chronic P. aeruginosa infection.

    Progression of Lung Function

    Univariate LMM analysis was used to examine interactions between repeated lung function measurements and age for evaluation of the progression of pulmonary dysfunction. As shown in Table 2, highest progression was found for FRCpleth (F = 22.3; p < 0.0001), LCI (F = 22.2; p < 0.0001), MEF50 (F = 20.2; p < 0.0001), and (F = 20.2; p < 0.0001). There was a strong sex difference for LCI. Whereas there was also a sex difference for FRCMBNW, the degree of the difference was less. For FVC and FEV1, secular trend had been included within the multivariate model. Progression of pulmonary dysfunction for some selected parameters is also given in Figure 1. The means of annual data changes for LCI, FEV1 and MEF50 are given showing highest slope and hence progression for LCI (0.58 ± 0.06; p < 0.0001) and lowest for FEV1 (eC0.18 ± 0.01; p < 0.0001). Taking the means as absolute values and applying the Bonferroni multiple comparison test, it can be shown that the highest differences were between FEV1 and LCI (t = 16.7; p < 0.001) and the lowest between MEF50 and FEV1 (t = 3.6; p < 0.01).

    Associations with confounding factors have been evaluated by multivariate LMM analysis, and also given in Table 2. Except for FRCMBNW, all lung function parameters were associated with onset of chronic P. aeruginosa infection. Highest F values were found for FEV1 (F = 9.1; p < 0.0001), and FVC (F = 8.0; p < 0.0001). Significance values for Bonferroni correction for multiple comparisons with a factor of 10 are indicated because 10 LMM analyses were included, and both the uncorrected p values and corrected significance levels (asterisks) are given in Table 2 because of the exploratory nature of the study.

    Sex Difference of LCI

    Table 2 demonstrates the observed sex difference for LCI and FRCMBNW. Progression of the LCI was significantly higher in females than in males (Figure 2). There were no correlations with any anthropometric parameter, such as z-scores of height, weight, ideal weight, body mass index, and weight for height, indicating that sex difference cannot be related to growth of these patients with CF. Sex difference could rather be explained by differences in the breathing pattern especially due to higher FRCMBNW in females (Figure 2, left panel), lower cumulative expired volume of the washout (Figure 2, middle panel), and hence lower ratio of FRC to cumulative expired volume, which represents by definition the LCI. Figure 2 in addition shows that after age 14 years, the PaCO2 declines in females in contrast to males (Figure 2, right panel), which may represent more clinically evident shallow breathing in females with CF.

    TimeeCEvent Relationship

    The evaluation of the time-event relationship for occurrence of abnormal lung function represented by each lung function parameter is given in Figure 3. The event was defined as the age when lung function data of two consecutive years were outside the normal predicted range of two standard deviations of the z-score. LCI presented the earliest index of abnormal lung function (median age of occurrence 6.3 years), followed by MEF50 (median of 7.2 years), and FVC (median of 7.8 years). The median age of onset for abnormal FEV1, FRCpleth, and VTG was 8.6, 8.9, and 13.0 years. Differences between all time-event curves were highly significant (p < 0.0001).

    Two-Test Comparison

    FEV1 is still considered one of the best predictors of progression in CF with many studies showing a steady downward course of FEV1 throughout life. In comparison, LCI and MEF50 represent the earliest indicators of abnormal lung function. Using z-score comparisons of concomitantly measured lung function parameters, Figure 4 presents the interrelationship between FEV1 and LCI (Figure 4A) and the interrelationship between MEF50 and LCI (Figure 4B). Agreement between FEV1 and LCI could be found in only 47.0% (conormal and coabnormal); however, agreement between MEF50 and LCI was found in 59.4% of the measurements. When FEV1 was normal (within a 2 SD-S range), LCI detected abnormal lung function (undetected by FEV1) in 52.5%; when FEV1 was abnormal (< eC2 SD-S), only 0.5% were undetected by LCI. Compared with FEV1, MEF50 showed less undetected cases in relation to the LCI (38.8 vs. 52.5%).

    Figure 5 demonstrates the influences of ventilation inhomogeneities and pulmonary hyperinflation on FEV1. The figures show changes of LCI and FRCpleth (bottom parts) in relation to FEV1 over time, the latter subdivided into subgroups depending on whether or not the patients presented with (A) ventilation inhomogeneities, or were (B) hyperinflated at the time of lung function testing. There is a continuous deterioration of LCI in parallel to FEV1 over time (Figure 5A). However, when related to pulmonary hyperinflation (Figure 5B), there was a decline of FEV1 only until the age of 12 years. After this age FEV1 remained unchanged despite the presence of progressively deteriorating lung disease as evidenced by an increase of ventilation inhomogeneities, pulmonary hyperinflation, and trapped gases in lung function.

    DISCUSSION

    This study is an attempt to evaluate progression of lung disease in CF based on repeated lung function measurement of changes of lung volume, airway obstruction, and ventilation distribution over a substantial time span. In addition, we aimed to fit interactions between the onset of chronic P. aeruginosa infection and genetic factors into a prediction model for lung function. We found that time-related changes of lung function have a strong interrelationship with progression of CF, which may be specific for the pathophysiologic processes involved in this disease. Pathophysiologic FEV1 is currently the gold standard for assessment of CF progression. Our data, however, suggest that inclusion of measurement of ventilation inhomogeneities within this model may add important information regarding disease progression. The present study gives new insight into the underlying long-term mechanisms responsible for determining the severity with which this process occurs.

    Progression of CF lung disease can be described objectively through the use of serial lung function tests. We showed that progression of lung disease is detected earliest by LCI (age median: 6.4 years), with MEF50 (age median: 7.2 years) being the next earliest predictor (Figure 2). We further demonstrated that FRCpleth, LCI, and MEF50 have the highest predictive value for deterioration in CF disease (Figure 1 and Table 2). Onset of Pseudomonas infection and CFTR genotype represent two more factors on which progression of lung disease depends (15, 16, 45eC49). The use of onset of chronic P. aeruginosa infection as an important marker of disease progression showed significant associations with all lung function parameters, except FRCMBNW. Genotype also showed a strong association with observed changes in FVC, and FEV1. On the basis of the above findings, we wish to discuss further aspects of longitudinal lung function evaluation and the role of current diagnostic tools used worldwide for routine evaluation of patients with CF.

    Limitations of the Methods

    The degree of lung pathology and its rate of progression are influenced by various confounding factors. In addition to genetic predisposition, improvements in the nutritional and pulmonary status resulting from improved multidisciplinary therapy may influence the severity of lung pathology. We searched carefully for such secular influences within our own data. The LMM model analyses revealed that two lung-function parameters (FVC: F = 11.370; p = 0.001 and FEV1: F = 6.548; p = 0.001) were influenced by secular trends. For both parameters, that influence was respected within the multivariate LMM analysis. Other potential confounders, such as chest physical therapy or nebulized rhDNase treatment, are factors that could not be included within the scope of this report. Nevertheless, it is worth noting that the Bernese Center closely followed the international guidelines of the North American CF Association, the European Working Group for CF, and hence, the European CF Society (24eC28, 50). Therefore, the present study can only report on disease progression in a collective of patients with CF studied over many years and in whom both medical and paramedical therapeutic regimens continued to improve as a whole. Moreover, the present study is based on a prospectively conducted database through which analysis was performed to determine the discriminative power of different lung function parameters collected serially. In contrast to the consensus paper of Ramsey and colleagues (15, 49, 51eC53), which deals with prospective interventional studies where the statistical concepts of primary outcome and thus of power calculation were important, the design of the present study did not permit such an analysis to be undertaken.

    Comparison of outcomes for patients with CF with early versus late diagnosis has demonstrated nutritional status as principal benefit within those diagnosed through neonatal screening (49, 54eC57). In contrast, assessment of pulmonary outcomes between these two groups has proven much more difficult (49, 54eC57). During the 1990s Kerem and coworkers showed that FEV1 was the variable best reflecting the status of lung function throughout the course of CF lung disease (4). Others demonstrated FEV1 to be the best predictor of mortality (16). However, despite the potential clinical importance of FEV1, increasing disagreement exists as to whether FVC and FEV1 alone should be used as outcome parameters for interventional decisions, such as lung transplantation (5, 57, 58). This may be especially important in cohorts of younger patients with CF. Highlighting the difficulties of measuring clinical outcome in young children with CF, Nixon and coworkers showed that increased morbidity seen with P. aeruginosa was not reflected by differences in FEV1 and FVC (59). Finally, analysis of FEV1 data from the CF Foundation Registry confirmed that most patients do not show overt evidence of airways obstruction until after 13 years of age (60). In the present study the median onset of abnormal FEV1 was 8.6 versus 6.4 years for LCI (Figure 3). Long-term evaluation of 64 patients with CF observed over a time span of 16 years was undertaken during the Wisconsin CF Neonatal Screening Project. After analysis of these data, Farrell and colleagues emphasized that airway obstruction is a relatively late sign of CF bronchopulmonary disease, and studies quantifying airflow at 75% of FVC exhalation and the residual volume/total lung capacity (RV/TLC) ratio in association with the hyperinflation score on chest radiographs failed to show evidence of peripheral airflow obstruction despite its potential clinical importance (13, 49). The finding that bronchial obstruction as measured by FEV1 occurs relatively late in the progression of lung disease in CF (60) is confirmed by the present study, although the median age for onset of an abnormal MEF50 was somewhat earlier (7.2 vs. 8.6 years). This finding is in agreement with Tiddens (48) who demonstrated reduced peripheral flows even in the presence of normal FEV1 as an early sign of substantial lung damage. Stratification of FEV1 data into subgroups characterized by pronounced ventilation inhomogeneities (Figure 5, left panel) or pulmonary hyperinflation (Figure 4B) demonstrates that FEV1 is influenced by the presence and degree of both these factors. Furthermore, Figure 5 demonstrates that the declines of FEV1 in the subgroups with pulmonary hyperinflation or ventilation inhomogeneities only continue until age 12 years. Thereafter, FEV1 remained relatively stable within the same lower range. This phenomenon is not new. Cooper and coworkers investigated variability of pulmonary function tests, including spirometric and plethysmographic measurements, in patients with CF. They emphasize that their finding of similarity between variability in mildly and severely affected patients may reflect clinically undetectable early changes in small airways long before conventional lung function parameters are affected. Moreover, it was hypothesized that children with more severe lung disease might reach a stage of fixed obstruction associated with reduced variability of airway caliber. This conclusion is confirmed by our study and may be best explained by unstable pressureeCflow behavior (61), a phenomenon that may strikingly interfere with lung function in patients with CF. The discussion concerning interaction between lung inflation, isovolume pressure-flow relations, and airway resistance is very complex. These interrelationships were initially elucidated by Bouhuys and Jonson (62) using a large number of breaths with different volume and flow histories obtained in healthy subjects. They showed that during expiration at small lung volumes, a flow plateau is reached within the isovolume pressureeCflow relationship. It was stated that beyond a certain point on the isovolume pressureeCflow relationship curve, flow rates are restricted due to suboptimal pressureeCflow conditions. In advanced stages of CF there is not only pulmonary hyperinflation with trapped gases, but also pulmonary restriction leading to very low lung volumes. We believe that patients depicted in the shaded areas of Figure 5 suffer from such limitations due to the driving pressure across the airways, especially when the thoraco-pulmonary system operates at near maximum flow, i.e., under conditions of dynamic compression of the intrathoracic airways. Therefore, it is not surprising that a high rate of subjects (52.5%) with abnormal lung function was not detected by FEV1 (Figure 4).

    Overall and peripheral inhomogeneity of ventilation was studied by Van Muylem and Baran (35). The authors stated that changes in the so-called "difference between sulfur hexafluoride and helium slope (SSP6 eC SHe) of Phase III on expiration" enabled the study of the time course of peripheral lung involvement in CF. It has been suggested that assessment using other possibly more specific indexes, such as the moment ratios (29, 30, 63, 64) or even the "dead-space corrected" and "alveolar-based" gas dilution number (65), may open a complete new field of sensitive and predictive lung function parameters.

    A relationship between CFTR genotype and severity of pulmonary disease in CF has proven difficult to establish (6, 8, 9, 66). It has, however, been recognized that in contrast to cross-sectional investigations, longitudinal analyses of lung function data using the LMM regression approach give a better statistical assessment in this context (16). Schaedel and coworkers used FEV1 in terms of percent predicted of normal to demonstrate a slower rate of decline in patients with missense mutations compared with F508(2) homozygotes (67). As these patients generally had a sufficient level of pancreatic function, it was concluded that CFTR genotypes associated with long-term pancreatic sufficiency have more benign lung disease and better pulmonary function (16, 67). With the exception of one patient with a missense mutation, all patients in this study presented with pancreatic insufficiency, requiring continuous supplementation with pancreatic enzymes and high caloric nutritional support. The interaction between CFTR genotype and lung involvement, previously investigated with respect to radiographic findings (68), was confirmed by the present study. FVC and FEV1 allow the best differentiation between CFTR groups, and all lung function parameters except FRCMBNW differentiate onset of chronic P. aeruginosa infection groups. These findings are in accordance with observations of Wilmott and coworkers who showed a strong association between P. aeruginosa status and mortality (69). Along the same line were associations between FEV1 and P. aeruginosa infection reported by Kerem and coworkers (68).

    The timing of lung transplantation and, therefore, the timing of referral for evaluation is yet critical and intensively debated, because premature referral and transplantation may compromise overall survival (4, 54, 70). Together with age, respiratory microbiology, height, annual number of hospital admissions, and courses of home intravenous antibiotics for pulmonary exacerbations, an FEV1 of less than 30% is the lung function parameter that is used in most CF transplant centers based on data from the CF National Patient Registry (60) and European Data Bases (71), using FEV1 alone as a single lung function parameter. In agreement with Liou and coworkers (72), Mayer-Hamblett and colleagues recently showed that transplant referral decisions based either on a multivariate logistic model or on the criterion of an FEV1 of less than 30% predicted are likely to result in high rates of premature referral. Moreover, the rate of decline in FEV1 failed to add any significant impact to a regression model (57). There is a need for better clinical predictors of short-term mortality among patients with CF. Although we have no sufficient experience with lung transplant referral and our observation range was up to age 20, we looked at the progression rate from the ages of 16 to 20 years. The slope of progression was still best for LCI (1.20 ± 0.15; p < 0.005) and worst for FEV1 (eC0.29 ± 0.08; p < 0.05). Therefore, although we have shown that LCI is one of the earliest and most sensitive lung function parameters in childhood, it could well also be of additional value later in life, especially for lung transplant referral decisions. At least the definition of "predictors of a model identifying patients for lung transplant referral" should no longer be restricted only to mechanical factors such as FVC and FEV1, and indices of intrapulmonary gas distribution should be introduced into databases.

    In summary, we have demonstrated that changes in static lung volumes, especially air trapping and the onset of ventilation distribution abnormalities, should be assessed as part of longitudinal follow-up of patients with CF. Furthermore, development of alternative techniques in addition to current flow-volume measurements appears to hold significant promise for the long-term assessment of respiratory function in this disease. The addition of washout techniques and whole-body plethysmography to standard spirometric tests may permit a more complete assessment of pulmonary involvement in CF. As a consequence, the interpretation of results of such investigations may improve our understanding of the underlying pathophysiologic processes. Finally, such information may prove crucial for future planning of clinical trials of new therapeutic strategies or in the assessment of risk factors for CF.

    Acknowledgments

    The authors thank Professor Martin H. Schni, M.D., Dr. Anna Re筪eberg, M.D., Dr. Carmen Casaulta Aebischer, M.D., and the entire nursing staff of the Bernese Cystic Fibrosis Clinic for their contribution in collecting the clinical data and in obtaining the samples for the genotype analysis. They also thank Mrs. Helen Gehr and Gisela Wirz for performing the lung function tests and taking care of the data base as well as Dr. Urs Frey, M.D., Ph.D. for critical appraisal of the manuscript and Dr. David Baldwin, M.D. for reviewing the manuscript and developing scientific English style.

    This article has an online supplement, which is accessible from this issue's table of contents online at www.atsjournals.org

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作者: Richard Kraemer, Andrea Blum, Andreas Schibler, Ro 2007-5-14
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