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Zystische Fibrose

Cystic fibrosis

  • Leitthema
  • Published:
Der Pneumologe Aims and scope

Zusammenfassung

Die zystische Fibrose (CF, syn.: Mukoviszidose) ist ein Musterbeispiel dafür, wie neue Erkenntnisse über ein Krankheitsbild zu einer kontinuierlichen Verbesserung der Therapie und Prognose genutzt wurden. Dennoch liegt der klinische Schwerpunkt bisher auf einer symptomatischen Behandlung, und weiterhin versterben 80% der CF-Patienten an den Folgen respiratorischer Insuffizienz. Die vorliegende Übersicht stellt aktuelles Wissen über die genetischen und molekularbiologischen Grundlagen der Erkrankung vor. Der Übergang des CF-Basisdefekts in eine klinisch manifeste Lungenerkrankung wird ausführlich diskutiert. Weiterhin werden Diagnostik- und Therapiestandards der Patientenversorgung in einem spezialisierten CF-Zentrum sowie mögliche zukünftige Therapieansätze vorgestellt. Es besteht die Hoffnung, dass das in den vergangenen Jahren erworbene multiprofessionelle Wissen über die CF-Erkrankung synergistisch genutzt werden kann, um bestehende Behandlungskonzepte weiter zu verbessern und am Basisdefekt orientierte Therapien zu entwickeln.

Abstract

Advances in knowledge and medical care of cystic fibrosis (CF) have resulted in a dramatic increase in life span and quality of life for this group of patients. Therapy remains, however, essentially symptomatic and the majority of patients faces premature death from respiratory failure. This review summarizes the current knowledge regarding the molecular basis of the CF gene and its product, CFTR. The pathways that link the malfunctioning of the CFTR protein with the observed pulmonary phenotype are discussed. State-of-the-art diagnostic and therapeutic standards performed in specialized German CF centers are introduced. There is hope that in the near future the accumulation of multiprofessional knowledge on CF disease will lead to improved therapeutic strategies, potentially targeting the basic defect.

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Literatur

  1. Anderson MP, Welsh MJ (1992) Regulation by ATP and ADP of CFTR chloride channels that contain mutant nucleotide-binding domains. Science 257: 1701–1704

    PubMed  Google Scholar 

  2. Balfour-Lynn IM, Klein NJ, Dinwiddie R (1997) Randomised controlled trial of inhaled corticosteroids (fluticasone propionate) in cystic fibrosis. Arch Dis Child 77: 124–130

    PubMed  Google Scholar 

  3. Balfour-Lynn IM, Lees B, Hall P et al. (2006) Multicenter randomized controlled trial of withdrawal of inhaled corticosteroids in cystic fibrosis. Am J Respir Crit Care Med

  4. Ballmann M, Smaczny C (1998) CF-Manual. Solvay Arzneimittel Hannover

  5. Ballmann M, Rabsch P, von der Hardt H (1998) Long-term follow up of changes in FEV1 and treatment intensity during Pseudomonas aeruginosa colonisation in patients with cystic fibrosis. Thorax 53: 732–737

    PubMed  Google Scholar 

  6. Bargon J, Stein J, Dietrich CF et al. (1999) Gastrointestinale Probleme erwachsener Patienten mit Cystischer Fibrose. Z Gastroenterol 37: 739–749

    PubMed  Google Scholar 

  7. Barker M, Hebestreit A, Gruber W et al. (2004) Exercise testing and training in German CF centers. Pediatr Pulmonol 37: 351–355

    Article  PubMed  Google Scholar 

  8. Brody AS, Tiddens HA, Castile RG et al. (2005) Computed tomography in the evaluation of cystic fibrosis lung disease. Am J Respir Crit Care Med 172: 1246–1252

    Article  PubMed  Google Scholar 

  9. Chmiel JF, Berger M, Konstan MW (2002) The role of inflammation in the pathophysiology of CF lung disease. Clin Rev Allergy Immunol 23: 5–27

    Article  PubMed  Google Scholar 

  10. Cohen RG, Starnes VA (2001) Living donor lung transplantation. World J Surg 25: 244–250

    Article  PubMed  Google Scholar 

  11. Colombo C, Battezzati PM, Strazzabosco M et al. (1998) Liver and biliary problems in cystic fibrosis. Semin Liver Dis 18: 227–235

    PubMed  Google Scholar 

  12. Conway SP, Pond MN, Bowler I et al. (1994) The chest radiograph in cystic fibrosis: a new scoring system compared with the Chrispin-Norman and Brasfield scores. Thorax 49: 860–862

    PubMed  Google Scholar 

  13. Doring G, Conway SP, Heijerman HG et al. (2000) Antibiotic therapy against Pseudomonas aeruginosa in cystic fibrosis: a European consensus. Eur Respir J 16: 749–767

    Article  PubMed  Google Scholar 

  14. Drumm ML, Konstan MW, Schluchter MD et al. (2005) Genetic modifiers of lung disease in cystic fibrosis. N Engl J Med 353: 1443–1453

    Article  PubMed  Google Scholar 

  15. Eigen H, Rosenstein BJ, FitzSimmons S et al. (1995) A multicenter study of alternate-day prednisone therapy in patients with cystic fibrosis. Cystic Fibrosis Foundation Prednisone Trial Group. J Pediatr 126: 515–523

    Article  PubMed  Google Scholar 

  16. Elkins MR, Robinson M, Rose BR et al. (2006) A controlled trial of long-term inhaled hypertonic saline in patients with cystic fibrosis. N Engl J Med 354: 229–240

    Article  PubMed  Google Scholar 

  17. Emerson J, Rosenfeld M, McNamara S et al. (2002) Pseudomonas aeruginosa and other predictors of mortality and morbidity in young children with cystic fibrosis. Pediatr Pulmonol 34: 91–100

    Article  PubMed  Google Scholar 

  18. Estenne M, Kotloff RM (2006) Update in transplantation 2005. Am J Respir Crit Care Med 173: 593–598

    Article  PubMed  Google Scholar 

  19. Ferrari S, Griesenbach U, Geddes DM et al. (2003) Immunological hurdles to lung gene therapy. Clin Exp Immunol 132: 1–8

    Article  PubMed  Google Scholar 

  20. Fuchs HJ, Borowitz DS, Christiansen DH et al. (1994) Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. The Pulmozyme Study Group. N Engl J Med 331: 637–642

    Article  PubMed  Google Scholar 

  21. Gibson RL, Emerson J, McNamara S et al. (2003) Significant microbiological effect of inhaled tobramycin in young children with cystic fibrosis. Am J Respir Crit Care Med 167: 841–849

    Article  PubMed  Google Scholar 

  22. Goetz M (2001) Fertilität bei CF-Patienten. In: Reinhardt D, Goetz M, Kraemer RH, Schoeni MH (Hrsg) Cystische Fibrose. Springer, Berlin Heidelberg New York Tokyo

  23. Grove JE, Lutzko C, Priller J et al. (2002) Marrow-derived cells as vehicles for delivery of gene therapy to pulmonary epithelium. Am J Respir Cell Mol Biol 27: 645–651

    PubMed  Google Scholar 

  24. Gysin C, Alothman GA, Papsin BC (2000) Sinonasal disease in cystic fibrosis: clinical characteristics, diagnosis, and management. Pediatr Pulmonol 30: 481–489

    Article  PubMed  Google Scholar 

  25. Haardt M, Benharouga M, Lechardeur D et al. (1999) C-terminal truncations destabilize the cystic fibrosis transmembrane conductance regulator without impairing its biogenesis. A novel class of mutation. J Biol Chem 274: 21873–21877

    Article  PubMed  Google Scholar 

  26. Hebestreit A, Kersting U, Basler B et al. (2001) Exercise inhibits epithelial sodium channels in patients with cystic fibrosis. Am J Respir Crit Care Med 164: 443–446

    PubMed  Google Scholar 

  27. Hirche TO, Atkinson JJ, Bahr S et al. (2004) Deficiency in neutrophil elastase does not impair neutrophil recruitment to inflamed sites. Am J Respir Cell Mol Biol 30: 576–584

    Article  PubMed  Google Scholar 

  28. Hirche TO, Loitsch S, Smaczny C et al. (2005) Neue Konzepte zur Pathophysiologie und Therapie der Mukoviszidose. Pneumologie 59: 811–818

    Article  PubMed  Google Scholar 

  29. Hirche TO, Smaczny C, von Mallinckrodt C et al. (2003) Pulmonale Manifestation der Mukoviszidose im Erwachsenenalter. Dtsch Arztebl 100: 264–270

    Google Scholar 

  30. Hodson ME, Gallagher CG, Govan JR (2002) A randomised clinical trial of nebulised tobramycin or colistin in cystic fibrosis. Eur Respir J 20: 658–664

    Article  PubMed  Google Scholar 

  31. Imundo L, Barasch J, Prince A et al. (1995) Cystic fibrosis epithelial cells have a receptor for pathogenic bacteria on their apical surface. Proc Natl Acad Sci USA 92: 3019–3023

    Article  PubMed  Google Scholar 

  32. Johnson LG, Boyles SE, Wilson J et al. (1995) Normalization of raised sodium absorption and raised calcium-mediated chloride secretion by adenovirus-mediated expression of cystic fibrosis transmembrane conductance regulator in primary human cystic fibrosis airway epithelial cells. J Clin Invest 95: 1377–1382

    PubMed  Google Scholar 

  33. Kelley TJ, Thomas K, Milgram LJ et al. (1997) In vivo activation of the cystic fibrosis transmembrane conductance regulator mutant deltaF508 in murine nasal epithelium. Proc Natl Acad Sci USA 94: 2604–2608

    Article  PubMed  Google Scholar 

  34. Kerem E, Conway S, Elborn S et al. (2005) Standards of care for patients with cystic fibrosis: a European consensus. J Cyst Fibros 4: 7–26

    Article  Google Scholar 

  35. Kerem E, Corey M, Kerem BS et al. (1990) The relation between genotype and phenotype in cystic fibrosis--analysis of the most common mutation (delta F508). N Engl J Med 323: 1517–1522

    PubMed  Google Scholar 

  36. Keswani SG, Crombleholme TM (2004) Gene transfer to the tracheobronchial tree: implications for fetal gene therapy for cystic fibrosis. Semin Pediatr Surg 13: 44–52

    Article  PubMed  Google Scholar 

  37. Knauer N, Ratjen F, Grasemann H (2005) Modifizierende Gene bei der zystischen Fibrose. Pneumologie 59: 395–404

    Article  PubMed  Google Scholar 

  38. Knowles MR, Boucher RC (2002) Mucus clearance as a primary innate defense mechanism for mammalian airways. J Clin Invest 109: 571–577

    Article  PubMed  Google Scholar 

  39. Konstan MW, Byard PJ, Hoppel CL et al. (1995) Effect of high-dose ibuprofen in patients with cystic fibrosis. N Engl J Med 332: 848–854

    Article  PubMed  Google Scholar 

  40. Konstan MW, Doring G, Lands LC et al. (2005) Results of a phase II clinical trial of BIIL 284 BS (an LTB4 receptor agonist) for the treatment of CF lung disease. Pediatr Pulmonol Suppl 28: 125–126

    Google Scholar 

  41. Konstan MW, Hillard KA, Koker P et al. (2003) Safety and tolerability of BIIL 284 BS (Amelubant), an oral once-daily LTB4 receptor antagonist, in adult and pediatric CF patients. Pediatr Pulmonol 24 [Suppl]: 259

  42. Lai HC, FitzSimmons SC, Allen DB et al. (2000) Risk of persistent growth impairment after alternate-day prednisone treatment in children with cystic fibrosis. N Engl J Med 342: 851–859

    Article  PubMed  Google Scholar 

  43. Liou TG, Adler FR, Cahill BC et al. (2001) Survival effect of lung transplantation among patients with cystic fibrosis. JAMA 286: 2683–2689

    Article  PubMed  Google Scholar 

  44. Matsui H, Grubb BR, Tarran R et al. (1998) Evidence for periciliary liquid layer depletion, not abnormal ion composition, in the pathogenesis of cystic fibrosis airways disease. Cell 95: 1005–1015

    Article  PubMed  Google Scholar 

  45. Milla CE, Warwick WJ (1998) Risk of death in cystic fibrosis patients with severely compromised lung function. Chest 113: 1230–1234

    PubMed  Google Scholar 

  46. Nilius B, Droogmans G (2003) Amazing chloride channels: an overview. Acta Physiol Scand 177: 119–147

    Article  PubMed  Google Scholar 

  47. Paul K, Rietschel E, Ballmann M et al. (2004) Effect of treatment with dornase alpha on airway inflammation in patients with cystic fibrosis. Am J Respir Crit Care Med 169: 719–725

    Article  PubMed  Google Scholar 

  48. Pier GB, Grout M, Zaidi TS et al. (1996) Role of mutant CFTR in hypersusceptibility of cystic fibrosis patients to lung infections. Science 271: 64–67

    PubMed  Google Scholar 

  49. Powell K, Zeitlin PL (2002) Therapeutic approaches to repair defects in deltaF508 CFTR folding and cellular targeting. Adv Drug Deliv Rev 54:1395–1408

    Article  PubMed  Google Scholar 

  50. Quinton PM (1990) Cystic fibrosis: a disease in electrolyte transport. FASEB J 4: 2709–2717

    PubMed  Google Scholar 

  51. Ramsey BW, Pepe MS, Quan JM et al. (1999) Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. Cystic Fibrosis Inhaled Tobramycin Study Group. N Engl J Med 340: 23–30

    Article  PubMed  Google Scholar 

  52. Ratjen F, Doring G, Nikolaizik WH (2001) Effect of inhaled tobramycin on early Pseudomonas aeruginosa colonisation in patients with cystic fibrosis. Lancet 358: 983–984

    Article  PubMed  Google Scholar 

  53. Ratjen F, Paul K, van Koningsbruggen S et al. (2005) DNA concentrations in BAL fluid of cystic fibrosis patients with early lung disease: influence of treatment with dornase alpha. Pediatr Pulmonol 39: 1–4

    Article  PubMed  Google Scholar 

  54. Ratjen F, Wonne R, Posselt HG et al. (1985) A double-blind placebo controlled trial with oral ambroxol and N- acetylcysteine for mucolytic treatment in cystic fibrosis. Eur J Pediatr 144: 374–378

    Article  PubMed  Google Scholar 

  55. Riordan JR, Rommens JM, Kerem B et al. (1989) Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 245: 1066–1073

    PubMed  Google Scholar 

  56. Rosenstein BJ, Cutting GR (1998) The diagnosis of cystic fibrosis: a consensus statement. Cystic Fibrosis Foundation Consensus Panel. J Pediatr 132: 589–595

    Article  PubMed  Google Scholar 

  57. Saiman L, Marshall BC, Mayer-Hamblett N et al. (2003) Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial. JAMA 290: 1749–1756

    Article  PubMed  Google Scholar 

  58. Selvadurai HC, Blimkie CJ, Meyers N et al. (2002) Randomized controlled study of in-hospital exercise training programs in children with cystic fibrosis. Pediatr Pulmonol 33: 194–200

    Article  PubMed  Google Scholar 

  59. Sheppard DN, Rich DP, Ostedgaard LS et al. (1993) Mutations in CFTR associated with mild-disease-form Cl- channels with altered pore properties. Nature 362: 160–164

    Article  PubMed  Google Scholar 

  60. Singh PK, Schaefer AL, Parsek MR et al. (2000) Quorum-sensing signals indicate that cystic fibrosis lungs are infected with bacterial biofilms. Nature 407: 762–764

    Article  PubMed  Google Scholar 

  61. Smith JJ, Travis SM, Greenberg EP et al. (1996) Cystic fibrosis airway epithelia fail to kill bacteria because of abnormal airway surface fluid. Cell 85: 229–236

    Article  PubMed  Google Scholar 

  62. Smyth A, Walters S (2003) Prophylactic antibiotics for cystic fibrosis. Cochrane Database Syst Rev CD001912

  63. Sokol RJ, Durie PR (1999) Recommendations for management of liver and biliary tract disease in cystic fibrosis. Cystic Fibrosis Foundation Hepatobiliary Disease Consensus Group. J Pediatr Gastroenterol Nutr 28 [Suppl]: 1–13

  64. Stein J, Jung M, Sziegoleit A et al. (1996) Immunoreactive elastase I: clinical evaluation of a new noninvasive test of pancreatic function. Clin Chem 42: 222–226

    PubMed  Google Scholar 

  65. Steinkamp G, Wiedemann B (2002) Relationship between nutritional status and lung function in cystic fibrosis: cross sectional and longitudinal analyses from the German CF quality assurance (CFQA) project. Thorax 57: 596–601

    Article  PubMed  Google Scholar 

  66. Stern M, Sens B, Wiedemann B et al. (2005) Qualitätsicherung Mukoviszidose – Überblick über den Gesundheitszustand der Patienten in Deutschland 2004. Zentrum für Qualitätsmanagement im Gesundheitswesen Hannover, http://www.muko.info

  67. Stover CK, Pham XQ, Erwin AL et al. (2000) Complete genome sequence of Pseudomonas aeruginosa PA01, an opportunistic pathogen. Nature 406: 959–964

    Article  PubMed  Google Scholar 

  68. Taylor CJ, Aswani N (2002) The pancreas in cystic fibrosis. Paediatr Respir Rev 3: 77–81

    Article  PubMed  Google Scholar 

  69. Trout L, King M, Feng W et al. (1998) Inhibition of airway liquid secretion and its effect on the physical properties of airway mucus. Am J Physiol 274: L258–L263

    PubMed  Google Scholar 

  70. Tsui LC, Durie P (1997) Genotype and phenotype in cystic fibrosis. Hosp Pract 32: 115–134

    Google Scholar 

  71. von Mallinckrodt C, Smaczny C, Hirche TO et al. (2005) Lungentransplantation bei Mukoviszidose. Atemw Lungenkrkh 31: 64–70

    Google Scholar 

  72. Wagner T, Soong G, Sokol S et al. (2005) Effects of azithromycin on clinical isolates of Pseudomonas aeruginosa from cystic fibrosis patients. Chest 128: 912–919

    Article  PubMed  Google Scholar 

  73. Ward CL, Kopito RR (1994) Intracellular turnover of cystic fibrosis transmembrane conductance regulator. Inefficient processing and rapid degradation of wild-type and mutant proteins. J Biol Chem 269: 25710–25718

    PubMed  Google Scholar 

  74. Wiedemann B, Paul K, Stern M et al. (2006) Evaluation of body mass index percentiles for assessment of malnutrition in children with cystic fibrosis. Eur J Clin Nutr (in press)

  75. Wood DM, Smyth AR (2006) Antibiotic strategies for eradicating Pseudomonas aeruginosa in people with cystic fibrosis. Cochrane Database Syst Rev CD004197

  76. Worlitzsch D, Tarran R, Ulrich M et al. (2002) Effects of reduced mucus oxygen concentration in airway Pseudomonas infections of cystic fibrosis patients. J Clin Invest 109: 317–325

    Article  PubMed  Google Scholar 

  77. Zabner J, Couture LA, Gregory RJ et al. (1993) Adenovirus-mediated gene transfer transiently corrects the chloride transport defect in nasal epithelia of patients with cystic fibrosis. Cell 75: 207–216

    Article  PubMed  Google Scholar 

  78. Zabner J, Smith JJ, Karp PH et al. (1998) Loss of CFTR chloride channels alters salt absorption by cystic fibrosis airway epithelia in vitro. Mol Cell 2: 397–403

    Article  PubMed  Google Scholar 

  79. Zar H, Saiman L, Quittell L et al. (1995) Binding of Pseudomonas aeruginosa to respiratory epithelial cells from patients with various mutations in the cystic fibrosis transmembrane regulator. J Pediatr 126: 230–233

    Article  PubMed  Google Scholar 

  80. Zielenski J (2000) Genotype and phenotype in cystic fibrosis. Respiration 67: 117–133

    Article  PubMed  Google Scholar 

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Danksagung

Die Autoren danken dem Wissenschaftlichen Beirat „Qualitätssicherung für Mukoviszidose“ für die Überlassung von Daten aus dem Berichtsband 2004 und würdigen die Leistung der Mitarbeiter der 111 deutschen CF-Ambulanzen, deren gewissenhafte Dokumentation eine Qualitätssicherung erst ermöglicht.

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  1. Schwerpunkt: Pneumologie/Allergologie, Klinikum der Johann Wolfgang Goethe-Universität, Theodor Stern Kai 7, 60590 , Frankfurt am Main, Deutschland

    T. O. Hirche, S. Loitsch, C. Smaczny, C. von Mallinckrodt & T. O. F. Wagner

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  1. T. O. Hirche
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  2. S. Loitsch
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  3. C. Smaczny
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  4. C. von Mallinckrodt
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  5. T. O. F. Wagner
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Correspondence to T. O. Hirche.

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Hirche, T.O., Loitsch, S., Smaczny, C. et al. Zystische Fibrose. Pneumologe 3, 325–339 (2006). https://doi.org/10.1007/s10405-006-0110-3

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