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Published ahead of print on March 17, 2004, doi:10.1164/rccm.200303-347OC
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American Journal of Respiratory and Critical Care Medicine Vol 169. pp. 1209-1216, (2004)
© 2004 American Thoracic Society

Original Article

Serial Lung Function and Responsiveness in Cystic Fibrosis during Early Childhood

Kim G. Nielsen, Tacjana Pressler, Bent Klug, Christian Koch{dagger} and Hans Bisgaard

Department of Pediatrics, Copenhagen University Hospital, Rigshospitalet; Department of Pediatrics, Copenhagen University Hospital, Hvidovre; Department of Pediatrics, Copenhagen University Hospital, Gentofte, Copenhagen, Denmark

Correspondence and requests for reprints should be addressed to Kim G. Nielsen, M.D., Department of Pediatrics, Pulmonary Service, 5003, Copenhagen University Hospital, Rigshospitalet, DK-2100 Copenhagen, Denmark. E-mail: kgn{at}dadlnet.dk


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 Conclusions
 REFERENCES
 
In a 4-year prospective study, we evaluated specific airway resistance (sRaw) by whole-body plethysmography, respiratory resistance by the interrupter technique, and respiratory resistance and reactance at 5 Hz by the impulse oscillation technique combined with measurement of responsiveness to bronchodilators and cold air in 30 children (mean [range] age 5.7 [2 to 8] years) with cystic fibrosis (CF). Spirometry was done at school age. Mean sRaw was consistently abnormal: the mean z score (SD) was 2.52 (2.02) (p < 0.001) at the start and was unchanged 36 months later at 2.74 (2.02). Mean z score (SD) for FEV1 at first satisfactory measurement, at a mean age (range) of 6.1 (4.9–7.5) years was –1.2 (1.2) and was further reduced to –1.85 (1.2) 4 years from inclusion at a mean age (range) of 9.9 (6.8–12) years. Neither respiratory resistance by the interrupter technique nor the impulse oscillation technique demonstrated consistent abnormal levels. Patients with CF as a group did not differ from healthy subjects in responsiveness to bronchodilators and cold air. sRaw may be a useful tool in CF during early childhood. Reduced lung function was documented from consistently abnormal levels of sRaw and FEV1 during the study. Bronchodilator responsiveness and response to cold air challenge were normal.

Key Words: cystic fibrosis • children • lung function

The lungs of children with cystic fibrosis (CF) are close to normal at birth, but early infection and inflammation lead to progressive lung destruction (1–3). Early detection of airway disease in infants and young children and longitudinal measurement of lung function (LF) may enable early intervention and improved prognosis. A significant reduction in LF has been found at a very early age (4–8), even in the absence of clinically recognized lung disease (9), and the degree of impaired LF appears to be correlated with the load of pathogens in the lower respiratory tract secretions (8). In our center, we observed that mean FEV1 was already reduced by 15–20% in 7-year-old patients with CF (unpublished). Studies on LF in children with CF in the preschool period are rare, as techniques used in infancy are not applicable and spirometry rarely produces reliable results in preschool children (10), although the latter has been challenged recently in cross-sectional studies demonstrating that application of computer animation programs may enhance the success rate (11–14). Techniques by which LF measurements are performed during normal tidal breathing in awake young children without requirement of reproducible forced maneuvers still attract special attention, and several techniques have been evaluated in our laboratory (15, 16). In this observational study, specific airway resistance (sRaw) by whole-body plethysmography, measurements of respiratory resistance and reactance at 5 Hz (Rrs5, Xrs5) by the impulse oscillation technique (IOS), and respiratory resistance measurements by the interrupter technique (Rint) were applied. We evaluated their usefulness in the assessment of LF in a cross-sectional and longitudinal study of a cohort of children with CF followed during early childhood and into school age, where spirometry was performed. Furthermore, we compared bronchodilator responsiveness (BDR) and bronchial responsiveness to cold air challenge (CACh) between children with CF and healthy young children (17, 18). The first cross-sectional dataset in this study has been previously reported in the form of abstracts (19, 20).


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 Conclusions
 REFERENCES
 
Patients with CF
Two- to 7-year-old children with a genotype diagnosis of CF were eligible for this study. Measurements were excluded if the child had any exacerbation in respiratory symptoms within the previous 3 weeks. Short- and long-acting ß2-agonists were withheld for 6 and 24 hours, respectively. Inhaled corticosteroids were allowed if the dosage was unchanged the previous month. If these conditions were not met, the visit was postponed 1 month. Our treatment strategy is described in detail elsewhere (21) and in an online supplement. The study was approved by the local ethics committee (KF 01–381/95), and written informed consent was obtained from the parents.

Healthy Subjects
Healthy children from our previous studies served as reference material for the baseline recordings (120 healthy subjects, 20 per year for the ages 2 to 7 years) (22), responsiveness to CACh (18), and BDR (17).

Design
This was a single-center observational, prospective, and longitudinal study. The clinician did not know measurement outcomes, and treatments were therefore not affected by the measurements. Likewise, the person conducting the LF tests was not biased by knowledge of the infection status of the patient. Patients attended the laboratory for seven visits (Figure 1) . Visits 2 and 6 were used for analysis of repeatability.



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  		Figure 1. Study timetable showing scheduled activity at each visit (open boxes = all patients, dashed boxes = patients more than 5 years if they met the criteria for acceptability). IOS = impulse oscillation technique; Rint = respiratory resistance measurements by the interrupter technique; sRaw = specific airway resistance.

 
LF was performed by one observer with a Master Screen unit 4.34 (Erich Jaeger GmbH, Würzburg, Germany). The equipment was calibrated daily. The pneumotachograph was changed and calibrated between patients to prevent cross-infection. Methods and equipment have previously been described in detail (15, 16, 23). Measurements were done in duplicate and in a fixed sequence (Rint -> sRaw -> IOS). FEV1 and FVC measurements were as per American Thoracic Society standards (24) using reference values from Polgar and Promadhat (25). Maximal efforts were encouraged by the use of computer animation.

BDR was assessed 20 minutes after administration of 500 µg of terbutaline inhaled from a pressurized metered dose inhaler via a metal spacer (Nebuchamber; ASTRA, Lund, Sweden) (17).

CACh was a single-step 4-minute isocapnic hyperventilation test using –15°C cold, dry air, mixed with 5% CO2, generated by a Respiratory Heat Exchange System (E. Jaeger GmbH, Würzburg, Germany) (18).

Statistical Analysis
LF values were expressed as z scores according to reference values (22, 25), equations given in the online supplement. A z score of +2 or –2 was used as the cutoff. Linear extrapolation was used to define reference values in children above 8. BDR and CACh response was quantified as the percentage change of the predicted value (17) and as a percentage change from baseline (18), respectively. Central tendency was expressed by mean and SD or range. A paired and unpaired t test was used to analyze BDR and CACh, with a power of more than 80% to detect relevant differences of 10% and 12%, respectively, for n = 30. Spearman and Wilcoxon rank sum tests were applied for analysis of tracking and changes between the beginning and the end of study. A linear mixed effects model was applied for analysis of trends, repeatability, and correlations of LF variables. Repeatability was also assessed from the calculation of the intraclass correlation coefficient and r2. A p value of less than 0.05 was used as the level of statistical significance.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 Conclusions
 REFERENCES
 
Thirty-nine patients with CF were eligible for the study. Nine patients did not participate: seven were noncompliant to one or more of the techniques more than once. One had Burkholderia cepacia and was isolated and not allowed to attend the laboratory. One did not comply with appointments. The remaining 30 patients (mean age [range] of 5.7 [2.7–7.7 years] at study entrance) were able to cooperate and performed satisfactorily on a reproducible series of LF tests. Six patients did not withhold ß2-agonists for the requested period before visit 2 and were not included in analysis of BDR for this visit. Six children were accompanied into the plethysmograph by a parent at visit 1 and four at visit 2. At all subsequent visits, all children managed plethysmographic measurements alone. Patient characteristics and summary of microbiology during study period are shown in Table 1 . All patients had had recurrent positive culture of Hemophilus influenzae in sputum and at least one positive culture and treatment of Staphylococcus aureus (data not shown).


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  		TABLE 1. Characteristics of the cystic fibrosis patients

 
LF (sRaw, Rint, Xrs5 and Rrs5): Cross-sectional and Longitudinal Perspective
Individual measurements by each method and by each of the yearly time points in the study are shown in Figure 2 and by age in Figure 3 . Mean sRaw was consistently and statistically significantly increased above normal levels throughout the study period. The mean (SD) z score for sRaw ranged from 1.95 (2.02) to 2.74 (2.02) (Table E3 in the online supplement). Only a minority was disclosed as having abnormal measurements using the other methods, and none of these methods exhibited any consistent abnormal pattern. The mean (SD) z score for Rint was within normal reference at all visits, except at 24 months after inclusion (Figure 2 and Table E3). Mean Rrs5 was statistically significantly reduced at visits 4 and 5 (Figure 2 and Table E3). Mean Xrs5 was abnormal at visit 1 (p = 0.042) because of one outlier but was normal throughout rest of the study period (Figure 2 and Table E3).



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  		Figure 2. Individual measurements expressed as z scores for each method (sRaw, Rint, Rrs5, Xrs5) and at each of the time points in the study are shown. *p < 0.05; **p < 0.001.

 


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  		Figure 3. Individual measurements expressed as z scores for each method (sRaw, Rint, Rrs5, Xrs5) and as function of age.

 
The number and percentage of patients within each category (low, normal, or high z score for each method) are given in Table E1 in online supplement. Between 37 and 57% of patients exhibited abnormal (high) sRaw at any visit. Table E2 in the online supplement shows how patients shifted category over time from Visit 1 to Visits 3, 4, 5, and 7, respectively. Approximately two-thirds of the patients were unchanged in category, independent of test or visit. The mean (SD) within-subject changes in z score for each parameter between visits are summarized in Table 2 . The within-subject changes between the beginning and the end of study were analyzed by the Spearman test (Table 3) , showing a statistically significant positive {rho} for all parameters, indicating that the order rank at end of study for all tests did not differ much from the order rank at inclusion. However, only individual values for Rint and Rrs5 generally changed during the study (Wilcoxon rank sum test; Table 3). Linear mixed effects model analysis with random factor subject, age at inclusion, and time in study at measurement as covariates gave slopes indicating the time dependence of each covariate on the z score of the LF variable (Table 4 ; see also Tables E3 to E6 in online supplement). sRaw and Xrs5 showed independence, whereas Rint and Rrs5 showed a statistically significant dependence of both covariates. Rint seemed positively dependent on time in study at measurement, but negatively dependent on age at inclusion. Rrs5 showed negative dependence on both covariates.


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  		TABLE 2. Mean (sd) within-subject change in Z score for each parameter between visit 1 and visits 3, 4, and 5, respectively (for fev1 between visit 4 and visits 5 and 7, respectively)

 

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  		TABLE 3. Analysis of within-subject change in z score between the first and last values using spearman correlation and wilcoxon signed rank sum test

 

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  		TABLE 4. Dependence of time in study (years) and age at inclusion (years) as fixed trends for each parameter (presented as z scores) evaluated by linear mixed effects model

 
Spirometry
Acceptable spirometry was possible for the first time at the mean age of 6.1 years (range, 4.9 to 7.5) showing a mean (SD) z score for FEV1 of –1.2 (1.2). Individual measurements expressed as z scores at each of the yearly time points in the study and by age of patient are shown in Figure 4 and means in Table E3 and E5. At 4 years from inclusion (visit 7), the z score was –1.85 (1.2) and was significantly lower than at the first measurement (p < 0.05). The percentage of patients with a z score of more than two below the expected FEV1 value varied between visits from 30 to 42% (Table E1), whereas only four patients (13%) had persistently low values at all visits. FEV1 showed statistically significant positive {rho} and individual change from visit 4 to visit 7 (Table 3).



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  		Figure 4. Spirometry. FEV1 expressed as z scores and (left) as function of time (months) since inclusion and (right) as function of age. **p < 0.001.

 
Correlations between Different LF Variables
Linear mixed effects model analyses (Table E8 in the online supplement) based on all relevant occasions gave statistically significantly linear correlations between sRaw and Rint and Xrs5 and Rrs5, respectively. Correlation was strongest between sRaw and Xrs5 (r2 = 0.75). We also found a correlation between FEV1 and sRaw (p = 0.028) with an r2 value of 0.80, whereas no significant correlation was found between FEV1 and the other methods.

LF and Repeatability within 1 Month
A presentation of repeatability within 1 month for each parameter is provided in the online supplement in Figures E1 to E3 and Table E7. The mean bias (SD) in z score for FEV1 between two baseline measurements 1 month apart (visits 5 and 6) was –0.06 (1.00) with an intraclass correlation coefficient of 83.3, whereas for comparison, the mean bias (SD) in z score for sRaw between two baseline measurements (visits 1 and 2) was 0.40 (1.78), not statistically significantly different from the bias of FEV1, but with a lower intraclass correlation coefficient of 64.7.

LF and Bacteriology
Pseudomonas aeruginosa had no detectable statistically significant influence on any LF tests when comparisons were made between patients who ever had had positive culturing of P. aeruginosa and those who never had. Episodes of persistent Staphylococcus aureus did not lead to a detectable influence on any LF either (data not shown).

BDR
Statistically significant BDR within group was demonstrated in all parameters at both visit 1 and visit 2; however, except for Xrs5 at visit 1 (p = 0.01), these mean changes were not different from BDR in a group of healthy subjects of 2 to 5 years (Figure 5) . Furthermore, mean sRaw remained abnormal at both visits, with a postbronchodilator z score of 0.98 (95% confidence interval, 0.38 to 1.57) and 0.90 (95% confidence interval, 0.29 to 1.50), respectively. A positive test was found in 30% and 21% at visits 1 and 2, respectively, as measured with sRaw, whereas correspondingly, 20% and 16% had a positive test measured with Xrs5. None or a very limited number of positive tests were seen with Rint and Rrs5.



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  		Figure 5. Bronchodilator responsiveness at visits 1 and 2 measured by sRaw, Rint, Xrs5, and Rrs5 and expressed as a change in percentage of predicted value. Solid lines indicate no change, dashed lines indicate cut-off levels, and horizontal bars indicate mean values. *p < 0.05; **p < 0.001. CF = cystic fibrosis.

 
CACh
The mean (SD) response to CACh within the group of patients with CF was 11.8% (17.8%) (p < 0.01) when measured with sRaw. Twenty-two percent of patients had a positive CACh test as measured by sRaw (data not shown). The response was 7.0% (11.5%) (p < 0.05) when measured with Rrs5. No significant change was seen in Rint (1.4% [10.9%]) and Xrs5 (–1.3% [27.4%]). However, the CACh response in the group of patients with CF and healthy subjects (18) did not differ when measured with any of the methods.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
Conclusions
 REFERENCES
 
This is the first prospective, longitudinal, and observational study report on serial LF measurements and bronchial responsiveness in patients with CF during early childhood. sRaw detected early abnormality in LF at inclusion (mean age of 5.7 years) and documented that this impairment was persistent in the group of patients involving between 37% and 57% of patients but did not progress during the study period. Spirometry obtained at school age (mean age of 9.8 years) confirmed these findings and was correlated with sRaw but showed a progressive reduction in FEV1. Repeatability of sRaw and FEV1 measurements within 1 month was equal. Progressive reduction in LF was also exhibited in Rint measurements, although most patients remained within normal levels. IOS provided less useful information. Our data also documented marked within-subject variability for all of the LF parameters and that a moderate tracking of LF values occurred over time. Neither BDR nor responsiveness to CACh as measured with sRaw was different from responsiveness seen in a group of healthy subjects, although some individuals exhibited positive tests.

This study highlights that a loss of LF occurs in the first few years of life, suggesting that there is a need for objective LF measurements in very early life, including infancy and young children, with a view to a more aggressive treatment approach before irreversible airway destructions have occurred. LF assessment is probably even more relevant in young children because early preventive measures against lung damage may have a more pronounced effect in this age group characterized by lung growth and development.

Serial and Cross-sectional LF Measurements
No single LF test has until now been able to assess reproducibly patients with CF in a serial fashion from infancy through preschool and school years. A large number of studies on LF testing in infants, extensively reviewed by Gappa and colleagues (7), have suggested that airway dysfunction and increased airway responsiveness are present early in the course of the lung disease. Recently, it was further emphasized that airway function is significantly reduced in infancy, even in those without clinically recognized previous lower respiratory illness (9).

This study assessed LF and airway responsiveness during early childhood in a serial fashion without a change in techniques. Our finding of a consistently abnormal sRaw in our cohort is supported by results from a study by Beardsmore (26), who reported a cross-sectional study of 29 patients with CF evaluated in infancy with body plethysmography measuring FRC, Raw, specific airway conductance, and rapid thoracoabdominal compression technique measuring maxFRC during sedation and followed at age 4 to 7 years with FVC, FEV1 and maximal expiratory flow (MEF25–50). She reported deterioration in LF before school age and found a significant correlation between the FRC score at different ages and reduced MEF25–50 at school age, however, with a change of methods from infancy to childhood. Recently, a cross-sectional study on spirometry in 33 3- to 6-year-old children with CF suggested that spirometry could be used successfully in the evaluation of LF in preschool children, and a significant reduction in FVC, FEV1, FEV1/FVC, and FEF25–75 was demonstrated (13) when compared with reference material (11). Thus, studies on LF in infancy (7, 9), in young children (13, 26), and in schoolchildren (27) support our observations.

sRaw, and to some extend Rint, but not IOS, detected abnormal LF in this group of children with CF. This advantage of sRaw was also found in previous studies in young children with asthma applying all three techniques (17, 18). The lack of ability of Rint and IOS to detect abnormality in patients with CF with abnormal spirometric values is in keeping with previous reports (28, 29). Underestimation of LF damage in CF was demonstrated in a study using the forced oscillation technique as a measurement of respiratory resistance in children with asthma or CF, concluding that the forced oscillation technique often failed to detect even severe airways obstruction in patients with CF but not in individuals with asthma (28). Hellinckx and colleagues (29) used the forced oscillation technique, plethysmography and spirometry to measure LF in 20 stable children with CF with a mean age of 12 years and found a poor relationship between FEV1 and Raw or Rrs6, whereas Xrs6 and FEV1/VC showed a weak correlation, suggesting that forced oscillation technique measurements could not replace baseline spirometric measurements in CF. Oswald-Mammosser and colleagues (30) measured respiratory resistance in 11-year-old children, 34 with CF and 47 with asthma, applying interrupter technique, plethysmography, and spirometry, and found in agreement with our study a similar tendency for Rint to underestimate airway obstruction in both groups, increasing with severity. One recent study (31) demonstrated the usefulness of expiratory Rint in the separation of healthy children and preschool children with CF but until now only in a cross-sectional design, whereas a longitudinal study should be performed to prove consistency.

In conclusion, we demonstrated the usefulness of serial measurements of sRaw to delineate abnormal LF through preschool to school age in children with CF. sRaw correlated with FEV1 and showed similar repeatability over 1 month. Rint underestimated airway obstruction in the majority of patients but revealed a tendency toward increasing abnormality within the normal range. IOS provided less useful information.

BDR
The efficacy of inhaled sympathomimetics on airway obstruction in CF has been shown in infants (5) school children and adults (32, 33). Hiatt and colleagues (5) demonstrated a significant change in maxFRC after metaproterenol in 28 infants and young children with CF compared with 22 normal control children and was able to eliminate the difference in baseline difference, which is in contrast to the study by Beydon and colleagues using Rint (31) and our results with sRaw finding no significant change compared with healthy and also persistent abnormal LF after ß2-agonist, which may suggest irreversible airway destruction. Daily treatment with bronchodilators and induction of tachyphylaxis may have influenced BDR in our patients. One-third did, however, exhibit positive BDR test with sRaw. Konig and colleagues (32) investigated the prevalence of the acute effect of bronchodilators in 21 patients with CF between 4 and 38 years in an open-label study. BDR of more than 15% was reported in 26% of patient days during 1 year of study. However, a randomized controlled trial designed to confirm any long-term effect on LF demonstrated a significant beneficial effect on spirometric data and hospitalization within the active treated group but failed to reach statistical significance when compared with the placebo group (33). Because forced expiration may cause paradoxical effect on unstable CF airways during FEV1 measurement, the forced oscillation technique, which is measured during quiet breathing, was suggested as an additional measure to spirometry in the evaluation of BDR in school children with CF (29). We did actually find statistically significant greater BDR in patients with CF compared with healthy subjects as measured with Xrs5 at visit 1, but this was probably a type I error because no significance was reached in any of the other measurements. In conclusion, BDR may be present in a subgroup of patients with CF and sRaw, and possibly also Xrs5 may prove valuable in disclosing such individuals.

Bronchial Hyperresponsiveness
The presence of bronchial hyperresponsiveness in patients with CF is generally considered an indication of a more aggressive pulmonary deterioration (34) and implies a response to treatment with inhaled corticosteroids (35). Between 21% and 56% of subjects with CF demonstrate significant responsiveness to a pharmacologic bronchial provocation test (36–38). In this study using a nonpharmacologic, indirect bronchial provocation test, bronchial hyperresponsiveness was shown in 22%, as measured with sRaw. This relatively higher proportion of bronchial hyperresponsiveness to pharmacologic tests may be explained from the pathophysiology of the CF lung, derived from inflammation leading to bronchopulmonary destruction and therefore a more unopposed bronchial constriction from the direct pharmacologic action on bronchial smooth muscles (39) in contrast to the indirect bronchoconstriction dependent on presence of and mediator release from certain inflammatory cells, which moreover are dependent on a proper stimulus such as exercise or CACh.

Different Properties of the Applied LF Tests
Different methods of LF measurement mirror different aspects of the lung and therefore different aspects of airway pathophysiology. Each method has its limitations and should be chosen depending on the compartment of interest (7). CF is a progressive disease with near-normal histology of airways postnatally but with very early progression of lung destruction (1, 2). Small airways exhibit plugging early in life leading to increased resistance and eventually, years later, into loss of volume. In fact, FVC in percentage of predicted remained unchanged in our study at a mean value of 100%, demonstrating the nonrestrictive nature of the disease in this relatively early phase. Increased sRaw measurement may reflect both airway obstruction and increased thoracic gas volume, and because CF does not result in central or upper airway obstruction, it is most likely that the results of our study reflect the early CF pathology of peripheral airways. However, because sRaw is dependent on both airway resistance and thoracic gas volume (sRaw = Raw x thoracic gas volume), sRaw will rise if either airway resistance increases or a possible hyperinflation appears or both. It is not possible to differentiate the effect of resistance or thoracic gas volume, but hyperinflation is most likely a consequence of increased resistance. The lack of volume measurement has previously been considered a limitation to this method, but calculation of sRaw from separate measurements of Raw and thoracic gas volume in a group of children with asthma gave similar results when measuring sRaw (40). Furthermore, in contrast to Xrs5, Rrs5, Rint, and FEV1, sRaw has the advantage of being practically independent of body size, with no significant correlation between age, weight, or height (22).

The interrupter technique measures a combination of the resistance of the airways, lung tissue, and chest wall (the total respiratory resistance) (41) and is based on the assumption that the respiratory system behaves like a single-compartment model presuming that equilibration between alveolar and mouth pressure is achieved within the occlusion period. Neither may be true in more severe airway obstruction, resulting in a multicompartment situation, and indeed time to reach equilibration may be much longer than 80 milliseconds in patients with CF with static obstruction. This may actually explain why most patients with CF had normal resistance in our and other studies (28) in contrast to the observation of abnormal Rint in young children with CF in the study by Beydon and colleagues (31), who chose to measure resistance during expiration and with an equilibration time of 100 milliseconds. Also, IOS is believed to measure the total respiratory resistance (42) but failed to disclose any baseline abnormality in our patients with CF in agreement with the observations by Hellinckx and colleagues (29) and also did not disclose any responsiveness to CACh.

Influence of Pulmonary Infection
Kerem and colleagues (27) demonstrated the influence of P. aeruginosa on LF deterioration: by the age of 7 years, the mean percentage predicted FEV1 was reduced by 10% in patients colonized with P. aeruginosa. In our study, we found a similar reduction of FEV1 at age 7, but only one patient was chronically colonized, whereas 47% were intermittently colonized. Nevertheless, we did not find any difference in any LF tests between patients who were never colonized and patients having had colonization with P. aeruginosa once or more. Similarly, we did not find any influence on LF from persistent S. aureus infection. However, both observations may be attributed to the small number of patients in this study (underpowered) and the fact that the study was not designed to look into concurrent specific infections and their treatments.

Future Perspectives
This study was designed to look for useful tools by which LF of young patients with CF may be evaluated in the future. The prestudy observation that FEV1 was already reduced by 15–20% in 7-year-old patients with CF was confirmed, emphasizing the need in the future to perform interventional studies in infants and young children using objective measurements as outcome. Gas washout techniques (43) also seem to be very sensitive options that should be explored for serial measurements in young children with CF. Furthermore, the early loss in LF suggests a need for a more aggressive approach in the treatment of infants and young children with CF. Multicenter cohort studies concentrating efforts on detecting causes of early inflammation whether preceded by infection, for example, by performing regular bronchoalveolar lavage and LF studies already from time of diagnosis are needed. The marked within-subject variability for all parameters in this study may limit their use in clinical management of individual patients. sRaw and FEV1 may serve as useful parameters in monitoring young children with CF; however, further research into standardization of these methods in this age group is strongly needed. Normal sRaw at the age of 2 to 5 years and normal FEV1 at the age of 6 to 7 years could probably function as endpoints in preventive measures against CF inflammation and should be possible to achieve in the future.

Limitations of the Study
There are certain limitations to our study. First, it is a small sample, which may have hampered results concerning the less sensitive methods, as well as results on bronchial hyperresponsiveness and influence of P. aeruginosa. Second, we do not have a reference material on the studied LF techniques for ages beyond 7 years, but because sRaw is age independent, this parameter was less likely to be hampered. Third, the reference material is based on cross-sectional observations, whereas our study is longitudinal. Finally, it would have strengthen our study if all methods, including spirometry, had been used from earlier on as suggested possible in recent studies (11, 13).


   Conclusions
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 Conclusions
REFERENCES
 
In conclusion, sRaw is useful as a serial measurement in CF during early childhood and was the most useful objective parameter showing loss of LF before inclusion, as suggested from the consistently abnormal level of the mean sRaw from time of inclusion and throughout the study. Rint and IOS were less useful. The pathophysiology of CF in this group of children neither caused increased BDR nor elicited a significant response to CACh. These results emphasize the need for an improved understanding of early CF pathology and eventually a more aggressive approach to therapy in infants and young children with CF. We suggest that sRaw and spirometry should be used as LF measures made from the age of 2 years and throughout childhood because these tests may be complementary in the description of the overall deterioration in LF.


   Acknowledgments
 
The authors thank biostatistician T. Bengtsson for helping with the statistical evaluation.


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

Conflict of Interest Statement: K.G.N. does not have a financial relationship with a commercial entity that has an interest in the subject of this article; T.P. does not have a financial relationship with a commercial entity that has an interest in the subject of this article; B.K. has participated as a speaker in meetings financed by various pharmaceutical companies; C.K. received lecture fees from Roche and Chiron of approximately $1,500 each year and received a fee approximately $1,500 in 2003 as an expert witness from Roche; H.B. has within the last 3 years received honoraria for lectures and attendance at pediatric advisory boards for Aerocrine, AstraZeneca, GlaxoSmithKline, Hoffman-La-Roche, Merck, Novartis, and Yamanouchi and holds no stock options in pharmaceutical industry in the respiratory field and owns a world patent for an inhaler device but receives no royalty and the COPSAC clinical research unit has in the last 3 years received research grants from the following industry partners in increasing order: Aerocrine, Merck, GSK, and AstraZeneca.

{dagger} Deceased. Back

Received in original form March 10, 2003; accepted in final form March 14, 2004


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 Conclusions
 REFERENCES
 

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