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Cystic Fibrosis FRACP teaching October 2007

Cystic Fibrosis FRACP teaching October 2007. Mark O’Carroll Respiratory Physician. Introduction. Mode of inheritence Genetic defect Pathology Pathophysiology Clinical features Diagnosis Therapy Survival. Cystic Fibrosis. The most common lethal inherited disease affecting Caucasians

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Cystic Fibrosis FRACP teaching October 2007

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  1. Cystic Fibrosis FRACP teaching October 2007 Mark O’Carroll Respiratory Physician

  2. Introduction • Mode of inheritence • Genetic defect • Pathology • Pathophysiology • Clinical features • Diagnosis • Therapy • Survival

  3. Cystic Fibrosis • The most common lethal inherited disease affecting Caucasians • Autosomal recessive • Incidence 1:2500 Caucasian populations • Carrier frequency 4% • Single gene disease (CFTR 7q) • Gene discovered 1989

  4. The CF gene: CFTR CFTR (7q) mRNA CFTR Protein CFTR Protein in Cell Membrane

  5. CFTR • Gene on 7q • 27 exons code for 1480 amino acid protein • Member of the ATP-binding cassette (ABC) family of transporters • Codes for a voltage gated chloride channel

  6. CFTR mutations • > 1000 mutations described • ∆F508 accounts for 70% • Certain mutations occur more frequently in particular ethnic groups • Commercially available genetic tests screen for the 31 most common mutations found in NZ population (accounts for 85% of the mutations)

  7. Pathology

  8. Normal Airway CF Airway

  9. Pathophysiology

  10. Molecular biology of CFTR • There has been considerable debate about the mechanism by which defective CFTR impacts on airway physiology and mucociliary clearance (MCC)

  11. The normal airway surface liquid layer

  12. Pathogenesis • Soon after birth there is intense neutrophilic inflammation in the CF lung • IL8 is the predominant cytokine and sentinel neutrophil chemo attractant • IL8 is produced by stimulated epithelial cells, macrophages and neutrophils • Various factors stimulate further IL8 production to sustain neutrophil influx (including IL1, TNF, LPS, Pseudomonas antigens and neutrophil elastase)

  13. Pathogenesis • TNF stimulates neutrophil secretory and oxidative processes • TNF and IL1 prime neutrophils for a heightened response to chemo attractants • Neutrophils then release massive amounts of elastase and other proteases which overwhelm local host defenses including 1AT and secretory leukocyte protease inhibitor (SLPI)

  14. Pathogenesis Neutrophil breakdown Large amounts high MW DNA  viscosity of endobronchial secretions  mucociliary clearance

  15. Classical Clinical Features ENT: Chronic Sinusitis Nasal Polyps Lungs: Cough and sputum Airflow obstruction Recurrent infection (Psa, S. aureus) GI: Pancreatic insufficiency (malnutrition) Pancreatitis (PS) Meconium ileus and DIOS Biliary cirrhosis and portal hypertension Sex organs: Obstructive azoospermia (CBAVD) Adapted from Welsh and Smith. Sci Am. 1995;273:52-59.

  16. Diagnosis of CFConsensus Statement J Pediatr 1998 One or more typical phenotypic features or a history of CF in a sibling or a positive newborn screening test plus Laboratory evidence of a CFTR abnormality [Sweat test, 2 CFTR mutations or NPD]

  17. CF Foundation Patient Registry 2003

  18. Therapy

  19. Correction of Underlying Defect Pharmacologic Therapy Gene Therapy Reduction in the Mucus Burden Airway Clearance Techniques Physical Training DN’ase Other Mucolytic Therapy Hyperosmolar Agents Control of Infection Nebulised anti-pseudomonal ABs IV anti-pseudomonal ABs Oral antibiotics Vaccination Long-term oral anti-staph ABs Control of Inflammation Oral corticosteroids ICS NSAIDs Macrolides Other Management Bronchodilators Theophylline LTRAs Flu vaccination LTOT NIV Lung transplantation Approach to the Management of CF Lung Disease

  20. Macrolides • Most significant recent advance in CF therapy • 3 RCTs (n=300 pts) + Cochrane review • All used azithromycin but probable class effect • Observed improvements in; • lung function • hospitalisation rate • intravenous antibiotic use • quality of life • weight

  21. Macrolides • Mechanism of action uncertain • Potential mechanisms; • Anti-inflammatory • Up-regulation of CFTR • Antibacterial effects   • Seem to work in patients without PsA infection • Appropriate use remains unclear Biofilm formation Quorum sensing Bacterial adherence

  22. A Controlled Trial of Long-Term Inhaled Hypertonic Saline in Patients with Cystic Fibrosis Mark R. Elkins, Michael Robinson, Barbara R. Rose, Colin Harbour, Carmel P. Moriarty, Guy B. Marks, Elena G. Belousova, Wei Xuan, and Peter T.P. Bye. NEJM 2006; 354(3): 229-240

  23. Study Overview • Patients with cystic fibrosis have inspissated mucus that is thought to contribute to the pulmonary exacerbations characteristic of the disease • As compared with treatment with normal saline, twice-daily treatment with inhaled hypertonic saline after the inhalation of a bronchodilator did not affect the linear rate of change in the forced expiratory volume in one second (FEV1) but was associated with improved FEV1 values and with fewer and shorter pulmonary exacerbations

  24. Absolute Change from Baseline in FVC (Panel A) and the FEV1 (Panel B) Elkins, M. et al. N Engl J Med 2006;354:229-240

  25. Effect of Hypertonic Saline on Lung Function Elkins, M. et al. N Engl J Med 2006;354:229-240

  26. Percentage of Participants in Each Group Remaining Free of Exacerbations during the Trial Elkins, M. et al. N Engl J Med 2006;354:229-240

  27. Conclusion Hypertonic saline preceded by a bronchodilator is an inexpensive, safe, and effective additional therapy for patients with cystic fibrosis

  28. Effect of Aerosolized Recombinant Human DN’ase on Exacerbations of Respiratory Symptoms and on Pulmonary Function in Patients with Cystic Fibrosis Henry J. Fuchs, Drucy S. Borowitz, David H. Christiansen, Edward M. Morris, Martha L. Nash, Bonnie W. Ramsey, Beryl J. Rosenstein, Arnold L. Smith, Mary Ellen Wohl, for The Pulmozyme Study Group NEJM 1994; 331: 637-642

  29. Fuchs et al. NEJM 1994

  30. Fuchs et al. NEJM 1994

  31. Intermittent Administration of Inhaled Tobramycin in Patients with Cystic Fibrosis Bonnie W. Ramsey, Margaret S. Pepe, Joanne M. Quan, Kelly L. Otto, A. Bruce Montgomery, Judy Williams-Warren, Michael Vasiljev-K, Drucy Borowitz, C. Michael Bowman, Bruce C. Marshall, Susan Marshall, Arnold L. Smith, for The Cystic Fibrosis Inhaled Tobramycin Study Group NEJM Ramsey et al. 1999; 340 (1): 23

  32. NEJM Ramsey et al. 1999; 340 (1): 23

  33. Survival

  34. Median survival age in cystic fibrosis, 1985–2001. Data from the U.S. Cystic Fibrosis Foundation Patient Registry. Median survival in 2001 was 33.4 years.

  35. Improved survival • Screening (early diagnosis) • Multi-disciplinary team based care • Nutritional supplementation • Better management of meconium ileus • Enhanced measures for sputum clearance • Improved antibiotics • Better management of respiratory failure • Transplantation

  36. Impact of FEV1 on survival Thorax 2001

  37. Impact of nutrition on survival Thorax 2001

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