Journal Mobile Options
Table of Contents
Vol. 75, No. 2, 2008
Issue release date: March 2008
Respiration 2008;75:178–181
(DOI:10.1159/000101725)

Long-Term Benefits of Inhaled Tobramycin in Children with Cystic Fibrosis: First Clinical Observations from Poland

Stelmach I.a · Korzeniewska A.a · Stelmach W.b
aDepartment of Pediatrics and Allergy, N. Copernicus Hospital and bN. Copernicus Hospital, Lodz, Poland
email Corresponding Author

Abstract

Background: Respiratory disease is the major cause of mortality in cystic fibrosis (CF) patients and inhaled antibiotic therapy may contribute to the stabilization of lung function. Objectives: This is a small, open, uncontrolled, observational study of clinical experience obtained with 2 years of maintenance treatment with inhaled tobramycin in 12 children and adolescents with CF. Methods: Twelve subjects aged 6–18 years infected by Pseudomonas aeruginosa were qualified for treatment with inhaled tobramycin. Pulmonary function, weight and height, clinical status, and chest X-ray were continually monitored. After an active 2-year treatment period, results of all measured parameters in our patients were compared with their previous results (2-year period before treatment with tobramycin). Results: During 2 years before treatment with tobramycin solution for inhalation (TOBI), pulmonary function decline was observed, the median value of FEV1 change was –7.6% (lower quartile –13.1, upper quartile –5.9). After 2 years of treatment, FEV1 percent predicted value declined by 1.5% (lower quartile –11.1, upper quartile 3.7) from baseline; 2 years of TOBI therapy significantly reduced lung function decline (p = 0.049). There were no significant changes in thoracic gas volume and specific airway resistance before and after treatment. Two years of TOBI therapy significantly improved body mass index (p = 0.02). TOBI treatment significantly delayed progression of pulmonary X-ray changes assessed by Brasfield score (p = 0.02). Conclusions: We found that patients with CF can gain substantial benefits from long-term TOBI treatment, including reduced pulmonary function decline, delayed progression of pulmonary X-ray changes and improved weight gain in growing children and adolescents.


 Outline


 goto top of outline Key Words

  • Cystic fibrosis
  • Inhaled drug therapy
  • Nutritional status
  • Pulmonary function tests
  • X-ray

 goto top of outline Abstract

Background: Respiratory disease is the major cause of mortality in cystic fibrosis (CF) patients and inhaled antibiotic therapy may contribute to the stabilization of lung function. Objectives: This is a small, open, uncontrolled, observational study of clinical experience obtained with 2 years of maintenance treatment with inhaled tobramycin in 12 children and adolescents with CF. Methods: Twelve subjects aged 6–18 years infected by Pseudomonas aeruginosa were qualified for treatment with inhaled tobramycin. Pulmonary function, weight and height, clinical status, and chest X-ray were continually monitored. After an active 2-year treatment period, results of all measured parameters in our patients were compared with their previous results (2-year period before treatment with tobramycin). Results: During 2 years before treatment with tobramycin solution for inhalation (TOBI), pulmonary function decline was observed, the median value of FEV1 change was –7.6% (lower quartile –13.1, upper quartile –5.9). After 2 years of treatment, FEV1 percent predicted value declined by 1.5% (lower quartile –11.1, upper quartile 3.7) from baseline; 2 years of TOBI therapy significantly reduced lung function decline (p = 0.049). There were no significant changes in thoracic gas volume and specific airway resistance before and after treatment. Two years of TOBI therapy significantly improved body mass index (p = 0.02). TOBI treatment significantly delayed progression of pulmonary X-ray changes assessed by Brasfield score (p = 0.02). Conclusions: We found that patients with CF can gain substantial benefits from long-term TOBI treatment, including reduced pulmonary function decline, delayed progression of pulmonary X-ray changes and improved weight gain in growing children and adolescents.

Copyright © 2007 S. Karger AG, Basel


goto top of outline Introduction

In cystic fibrosis (CF), immune-mediated inflammation and chronic airway infections contribute to progressive pulmonary tissue damage. The relationship between chronic infection, decline in pulmonary function and mortality has been described before [1,2,3,4]. Pseudomonas aeruginosa is the most frequent pathogen isolated from CF sputum or bronchoalveolar lavage. In chronically infected patients, inhaled antibiotic therapy may contribute to the stabilization of lung function; besides aminoglycosides, β-lactam antibiotics and colistin have been used [5]. Over the last 10 years a new formulation of tobramycin has been developed for inhaled therapy. Significant improvements in lung function, nutritional status and health-related quality of life, reduced hospitalization rates and decreased density of P. aeruginosa in sputum samples after nebulized tobramycin administered twice daily have been described [6,7,8]. Tobramycin solution for inhalation (TOBI; Chiron, Emeryville, Calif., USA) was registered in Poland in 2004; previously patients had required an agreement from the Health Ministry for drug import.

This is a small, open, uncontrolled, observational study of clinical experience obtained with 2 years of maintenance treatment with inhaled tobramycin in 12 children and adolescent patients with CF.

 

goto top of outline Materials and Methods

Twelve subjects with CF, aged 6–18 years, were qualified for treatment with inhaled tobramycin. In order to be included for treatment, the patients had to have documented chronic P. aeruginosa infection and moderate to severe lung disease with forced expiratory values in 1 s (FEV1) of 25–75% of predicted values. Three patients with FEV1 higher than 75% of the predicted value were also qualified for treatment: 2 patients with bronchohyperreactivity for colistin and ceftazidime as well as 1 patient with liver cirrhosis waiting for transplantation. Exclusion criteria included significant hemoptysis, significant hypoxemia (partial pressure of oxygen less than 60 mm Hg), hypersensitivity to aminoglycosides, recent pulmonary exacerbation, impaired renal function and presence of Burkholderia cepacia. The treatment consisted of 300 mg of aerolized tobramycin delivered twice daily in a series of cycles consisting of 28 days of treatment (‘on drug’) followed by 28 days without treatment (‘off drug’). Eight patients started the treatment in 2003 and 4 patients in 2004. During tobramycin treatment, all patients were treated with dornase alfa; azithromycin, inhaled corticosteroids and β2-agonists were taken periodically by 8 patients. All patients had pancreatic insufficiency; they were taking pancreatic enzymes and vitamins. Pulmonary function, weight and height, clinical status, and occurrence of adverse events were continually monitored after each cycle. Chest X-rays were performed at the start of the treatment and after 1 and 2 years of treatment. After the active treatment period, results of all measured parameters in our patients were compared with their previous results (2 years before treatment with tobramycin).

FEV1, thoracic gas volume (TGV) and specific airway resistance (sRaw) were measured using a whole-body plethysmograph (Lungtest 1000; MES, Krakow, Poland). The tests were performed according to European Respiratory Society guidelines [9]. Before lung function testing, β2-agonists were withheld for 12 h. The relative changes in the percentage of the predicted values of lung function parameters were calculated by comparing the values measured 2 years before treatment and to those after 2 years of treatment with TOBI.

Body mass index (BMI) was calculated as weight (in kilograms) divided by the square of height (in meters) and given with SD scores for the Lodz population [10].

Chest X-rays were evaluated using the Brasfield score [11]. Patient characteristics are given in table 1.

TAB01
Table 1. Patient baseline characteristics

goto top of outline Statistical Analysis

The results were analyzed according to well-known statistical methods by using StatSoft Statistica for Windows, release 6.0 (StatSoft Inc., Tulsa, Okla., USA). Data are presented as medians with lower/upper quartile values in parentheses. To compare changes with treatment between 2 years before and 2 years after tobramycin therapy, all parameters were analyzed using the Wilcoxon test. For all patients, Brasfield scores before and after treatment were deducted and compared between 2 years before and 2 years after tobramycin therapy using Fisher’s exact two-tailed tests. p < 0.05 was considered to be significant.

 

goto top of outline Results

During 2 years before treatment with TOBI, a pulmonary function decline was observed, FEV1 change was –7.6% (–13.1, –5.9). At the end of the first year of treatment, FEV1 percent predicted value increased by 3.8% (1.4, 5.2) from baseline. After the second year of treatment, FEV1 percent predicted value declined by 1.5% (–11.1, 3.7) from baseline (fig. 1). Two years of TOBI therapy significantly (p = 0.049) reduced lung function decline. There were no significant changes in TGV and sRaw before and after treatment.

FIG01
Fig. 1. Comparison between changes in FEV1 (percentage of predicted value) during the 2-year period before treatment and the 2-year period of tobramycine treatment. Data are presented as median values with quartile ranges.

During the 2-year period before TOBI therapy, median BMI increased by 0.3 (0.1, 0.4). After 2 years of treatment, median BMI increased by 0.98 (0.4, 1.8). Two years of TOBI therapy significantly improved BMI (p = 0.02; fig. 2).

FIG02
Fig. 2. Comparison between changes in BMI during 2 years before tobramycine treatment and 2 years of tobramycine treatment. Data are presented as median values with quartile ranges.

TOBI treatment significantly delayed progression of pulmonary X-ray changes assessed by Brasfield score (p = 0.02; fig. 3).

FIG03
Fig. 3. Changes in Brasfield score 2 years before and 2 years after treatment with tobramycin. –3 = Worsening in Brasfield score by 3 points; –2 = worsening in Brasfield score by 2 points; –1 = worsening in Brasfield score by 1 point; 0 = no change in Brasfield score; 1 = improvement in Brasfield score by 1 point; 2 = improvement in Brasfield score by 2 points.

 

goto top of outline Discussion

Pulmonary function is the single best predictor of morbidity and mortality in CF patients [2]. Reduced pulmonary function decline improves the life expectancy and quality of life for CF patients [12]. Significant improvement in lung function after therapy with nebulized tobramycin has been previously described [6, 7, 13], but long-term trials (lasting more then 2 years) are still lacking. This was the largest single-center group of patients treated with TOBI in Poland. We observed reduced pulmonary function decline in CF patients after 2 years of treatment with TOBI. Improvement in lung function was observed after the first year of treatment, followed by a slow decline. This finding is consistent with that of Grzincich et al. [14], who also showed improvement in pulmonary function in the first year and deterioration in the second year of treatment with TOBI. This waning effect of the treatment could be related to antibiotic resistance. Infection with multiple-antibiotic-resistant P. aeruginosa is associated with accelerated progression of CF [15, 16]. We did not assess antibiotic minimal inhibitory concentration, but clinical response to TOBI in patients with CF did not appear to be affected by tobramycin minimal inhibitory concentration [6, 7]. The other explanation for that phenomenon could be that the patients may not comply with the treatment regime. We found no significant changes in TGV and sRaw, and this could be explained by the fact that tobramycin has no effect on consolidate lung tissue damage and hyperinflation which appears to be irreversible. To our knowledge, there are no published data on the effect of inhaled tobramycin treatment on airway resistance or chest X-ray in CF patients. Significant correlations between chest radiograph scores and lung function have been observed in many studies in children and adults, but not all the variability in X-ray scores is explained by lung function measurements. Spirometry appears more sensitive in detecting changes in pulmonary status, and the decline in FEV1 may be twice that of the chest X-ray score [17, 18]. We observed significantly delayed progression of pulmonary X-ray changes and reduced pulmonary function decline after long-term treatment with tobramycin.

Poor clinical outcomes are associated with undernutrition in CF patients; body weight is an important prognostic factor and has been associated with survival [19,20,21]. Our findings are consistent with those of Moss [7] and suggest that long-term antipseudomonal aerolized antibiotic therapy can improve weight gain in CF patients. We have not seen any nonresponders for at least 1 parameter in the first and the second year of therapy. For all patients it was a valuable adjunct therapy.

In our center, the number of individuals with CF older than 6 years and chronically infected with P. aeruginosa is too small to conduct a study with a parallel nontreated group, therefore we could not evaluate potential differences in disease progression.

In conclusion, we found that patients with CF can gain substantial benefits from long-term TOBI treatment, including reduced pulmonary function decline, delayed progression of pulmonary X-ray changes and improved weight gain in growing children and adolescents.


 goto top of outline References
  1. Henry RL, Mellis CM, Petrovic L: Mucoid Pseudomonas aeruginosa is a marker of poor survival in cystic fibrosis. Pediatr Pulmonol 1992;12:158–161.
  2. Kerem E, Reisman J, Corey M, Canny GJ, Levison H: Prediction of mortality in patients with cystic fibrosis. N Engl J Med 1992;326:1187–1191.
  3. Gustafsson PM: Commentary: early looks into the ‘silent lung zones’ of young subjects with cystic fibrosis. Respiration 2000;67:489–490.
  4. Koch C, Høiby N: Diagnosis and treatment of cysticfibrosis. Respiration 2000;67:239–247.
  5. Frederiksen B, Koch C, Hoiby N: Antibiotic treatment of initial colonization with Pseudomonas aeruginosa postpones chronic infection and prevents deterioration of pulmonary function in cystic fibrosis. Pediatr Pulmonol 1997;5:330–335.

    External Resources

  6. Ramsey BW, Pepe MS, Quan JM, Otto KL, Montgomery AB, Williams-Warren J, Vasiljev-K M, Borowitz D, Bowman CM, Marshall BC, Marshall S, Smith AL: Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. Cystic Fibrosis Inhaled Tobramycin Study Group. N Engl J Med 1999;340:23–30.
  7. Moss RB: Long-term benefits of inhaled tobramycin in adolescent patients with cystic fibrosis. Chest 2002;121:55–63.
  8. Bowman CM: The long-term use of inhaled tobramycin in patients with cystic fibrosis. J Cyst Fibros 2002;1:194–198.
  9. European Respiratory Society Working Party: Standardization of lung function testing. Eur Respir J 1993;6(suppl):5–100.
  10. Malinowski A, Chlebna-Sokol D: Lodz Child: Study Methods and Reference Values of Biological Development. Lodz, Ankal, 1998.
  11. Brasfield D, Hilks G, Soong S, Tiller RE: The chest roentgenogramin cystic fibrosis: a new scoring system. Pediatrics 1979;63:23–29.
  12. Quittner AL, Buu A: Effects of tobramycin solution for inhalation on global ratings of quality of life in patients with cystic fibrosis and Pseudomonas aeruginosa infection. Pediatr Pulmonol 2002;33:269–276.
  13. Hodson ME, Gallagher CG, Govan JR: A randomised clinical trial of nebulised tobramycin or colistin in cystic fibrosis. Eur Respir J 2002;20:658–664.
  14. Grzincich GL, Miano A, Pisi G, Spaggiari C, Tripodi MC: Effect of TOBI continuous therapy on pulmonary function in CF patients. J Cyst Fibros 2005;4:S53.

    External Resources

  15. Lechtzin N, John M, Irizarry R, Merlo C, Diette GB, Boyle MP: Outcomes of adults with cysticfibrosis infected with antibiotic-resistant Pseudomonas aeruginosa. Respiration 2006;73:27–33.
  16. Aaron SD: Pseudomonas aeruginosa and cystic fibrosis - a nasty bug gets nastier. Respiration 2006;73:16–17.
  17. Koscik RE, Kosorok MR, Farrell PM, Collins J, Peters ME, Laxova A, Green CG, Zeng L, Rusakow LS, Hardie RC, Campbell PW, Gurney JW: Wisconsin cystic fibrosis chest radiograph scoring system: validation and standardization for application to longitudinal studies. Pediatr Pulmonol 2000;29:457–467.
  18. Terheggen-Lagro S, Truijens N, van Poppel N, Gulmans V, van der Laag J, van der Ent C: Correlation of six different cystic fibrosis chest radiograph scoring systems with clinical parameters. Pediatr Pulmonol 2003;35:441–445.
  19. Bell SC, Bowerman AR, Davies CA, Campbell IA, Shale DJ, Elborn JS: Nutrition in adults with cystic fibrosis. Clin Nutr 1998;17:211–215.
  20. Bakker W: Nutritional state and lung disease in cystic fibrosis. Neth J Med 1992;41:130–136.
  21. Kraemer R, Aebi C, Aebischer CC, Gallati S: Early detection of lung disease and its association with the nutritional status, genetic background and life events in patients with cystic fibrosis. Respiration 2000;67:477–490.

 goto top of outline Author Contacts

Iwona Stelmach, MD, PhD
62 Pabianicka Str.
93-513 Lodz (Poland)
Tel. +48 42 689 59 72, Fax +48 42 689 59 73
E-Mail alergol@kopernik.lodz.pl


 goto top of outline Article Information

Received: November 23, 2005
Accepted after revision: February 1, 2007
Published online: April 13, 2007
Number of Print Pages : 4
Number of Figures : 3, Number of Tables : 1, Number of References : 21


 goto top of outline Publication Details

Respiration (International Journal of Thoracic Medicine)

Vol. 75, No. 2, Year 2008 (Cover Date: March 2008)

Journal Editor: Bolliger, C.T. (Cape Town)
ISSN: 0025–7931 (Print), eISSN: 1423–0356 (Online)

For additional information: http://www.karger.com/RES


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Background: Respiratory disease is the major cause of mortality in cystic fibrosis (CF) patients and inhaled antibiotic therapy may contribute to the stabilization of lung function. Objectives: This is a small, open, uncontrolled, observational study of clinical experience obtained with 2 years of maintenance treatment with inhaled tobramycin in 12 children and adolescents with CF. Methods: Twelve subjects aged 6–18 years infected by Pseudomonas aeruginosa were qualified for treatment with inhaled tobramycin. Pulmonary function, weight and height, clinical status, and chest X-ray were continually monitored. After an active 2-year treatment period, results of all measured parameters in our patients were compared with their previous results (2-year period before treatment with tobramycin). Results: During 2 years before treatment with tobramycin solution for inhalation (TOBI), pulmonary function decline was observed, the median value of FEV1 change was –7.6% (lower quartile –13.1, upper quartile –5.9). After 2 years of treatment, FEV1 percent predicted value declined by 1.5% (lower quartile –11.1, upper quartile 3.7) from baseline; 2 years of TOBI therapy significantly reduced lung function decline (p = 0.049). There were no significant changes in thoracic gas volume and specific airway resistance before and after treatment. Two years of TOBI therapy significantly improved body mass index (p = 0.02). TOBI treatment significantly delayed progression of pulmonary X-ray changes assessed by Brasfield score (p = 0.02). Conclusions: We found that patients with CF can gain substantial benefits from long-term TOBI treatment, including reduced pulmonary function decline, delayed progression of pulmonary X-ray changes and improved weight gain in growing children and adolescents.



 goto top of outline Author Contacts

Iwona Stelmach, MD, PhD
62 Pabianicka Str.
93-513 Lodz (Poland)
Tel. +48 42 689 59 72, Fax +48 42 689 59 73
E-Mail alergol@kopernik.lodz.pl


 goto top of outline Article Information

Received: November 23, 2005
Accepted after revision: February 1, 2007
Published online: April 13, 2007
Number of Print Pages : 4
Number of Figures : 3, Number of Tables : 1, Number of References : 21


 goto top of outline Publication Details

Respiration (International Journal of Thoracic Medicine)

Vol. 75, No. 2, Year 2008 (Cover Date: March 2008)

Journal Editor: Bolliger, C.T. (Cape Town)
ISSN: 0025–7931 (Print), eISSN: 1423–0356 (Online)

For additional information: http://www.karger.com/RES


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Henry RL, Mellis CM, Petrovic L: Mucoid Pseudomonas aeruginosa is a marker of poor survival in cystic fibrosis. Pediatr Pulmonol 1992;12:158–161.
  2. Kerem E, Reisman J, Corey M, Canny GJ, Levison H: Prediction of mortality in patients with cystic fibrosis. N Engl J Med 1992;326:1187–1191.
  3. Gustafsson PM: Commentary: early looks into the ‘silent lung zones’ of young subjects with cystic fibrosis. Respiration 2000;67:489–490.
  4. Koch C, Høiby N: Diagnosis and treatment of cysticfibrosis. Respiration 2000;67:239–247.
  5. Frederiksen B, Koch C, Hoiby N: Antibiotic treatment of initial colonization with Pseudomonas aeruginosa postpones chronic infection and prevents deterioration of pulmonary function in cystic fibrosis. Pediatr Pulmonol 1997;5:330–335.

    External Resources

  6. Ramsey BW, Pepe MS, Quan JM, Otto KL, Montgomery AB, Williams-Warren J, Vasiljev-K M, Borowitz D, Bowman CM, Marshall BC, Marshall S, Smith AL: Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. Cystic Fibrosis Inhaled Tobramycin Study Group. N Engl J Med 1999;340:23–30.
  7. Moss RB: Long-term benefits of inhaled tobramycin in adolescent patients with cystic fibrosis. Chest 2002;121:55–63.
  8. Bowman CM: The long-term use of inhaled tobramycin in patients with cystic fibrosis. J Cyst Fibros 2002;1:194–198.
  9. European Respiratory Society Working Party: Standardization of lung function testing. Eur Respir J 1993;6(suppl):5–100.
  10. Malinowski A, Chlebna-Sokol D: Lodz Child: Study Methods and Reference Values of Biological Development. Lodz, Ankal, 1998.
  11. Brasfield D, Hilks G, Soong S, Tiller RE: The chest roentgenogramin cystic fibrosis: a new scoring system. Pediatrics 1979;63:23–29.
  12. Quittner AL, Buu A: Effects of tobramycin solution for inhalation on global ratings of quality of life in patients with cystic fibrosis and Pseudomonas aeruginosa infection. Pediatr Pulmonol 2002;33:269–276.
  13. Hodson ME, Gallagher CG, Govan JR: A randomised clinical trial of nebulised tobramycin or colistin in cystic fibrosis. Eur Respir J 2002;20:658–664.
  14. Grzincich GL, Miano A, Pisi G, Spaggiari C, Tripodi MC: Effect of TOBI continuous therapy on pulmonary function in CF patients. J Cyst Fibros 2005;4:S53.

    External Resources

  15. Lechtzin N, John M, Irizarry R, Merlo C, Diette GB, Boyle MP: Outcomes of adults with cysticfibrosis infected with antibiotic-resistant Pseudomonas aeruginosa. Respiration 2006;73:27–33.
  16. Aaron SD: Pseudomonas aeruginosa and cystic fibrosis - a nasty bug gets nastier. Respiration 2006;73:16–17.
  17. Koscik RE, Kosorok MR, Farrell PM, Collins J, Peters ME, Laxova A, Green CG, Zeng L, Rusakow LS, Hardie RC, Campbell PW, Gurney JW: Wisconsin cystic fibrosis chest radiograph scoring system: validation and standardization for application to longitudinal studies. Pediatr Pulmonol 2000;29:457–467.
  18. Terheggen-Lagro S, Truijens N, van Poppel N, Gulmans V, van der Laag J, van der Ent C: Correlation of six different cystic fibrosis chest radiograph scoring systems with clinical parameters. Pediatr Pulmonol 2003;35:441–445.
  19. Bell SC, Bowerman AR, Davies CA, Campbell IA, Shale DJ, Elborn JS: Nutrition in adults with cystic fibrosis. Clin Nutr 1998;17:211–215.
  20. Bakker W: Nutritional state and lung disease in cystic fibrosis. Neth J Med 1992;41:130–136.
  21. Kraemer R, Aebi C, Aebischer CC, Gallati S: Early detection of lung disease and its association with the nutritional status, genetic background and life events in patients with cystic fibrosis. Respiration 2000;67:477–490.