Cystic Fibrosis 2

• Treatment for Cystic Fibrosis

  • Reducing Airway Obstruction
  • Controlling Infection
  • Controlling Inflammation
  • Correcting the Basic Defect
  • Lung Transplantation
• Reducing Airway Obstruction


  1. Chest Physiotherapy

  2. Bronchodilators

  3. Mucolytics
• Controlling Infection


  Antibiotics
• Controlling Inflammation


  1. Corticosteroids

  2. NSAIDS

  3. Anti-Proteases
• Correcting the Basic Defect

  1. Gene Therapy

  2. Activation of Mutant CFTR

  3. Manipulation of Ion Transport
• Lung Transplantation


  • Lung
  • Heart-Lung
  • Bi-lobar, living donor
• Excessive Mucus


  • Reduces airflow
  • Invites infection
  • Restricts the delivery of other inhaled drugs, including gene therapy vectors
• Chest Physiotherapy is the Corner Stone of Treatment
• Chest Physiotherapy


  1. Postural drainage

  2. Chest percussion and vibration, manually or with a mechanical percussor

  3. Newer techniques and devices, such as the high frequency chest oscillation therapy vest
• Bronchodilators


  Usually beta-adrenergic agonists, or cholinergic blockers, nebulised and inhaled prior to chest physiotherapy to dilate small airways and facilitate mucus clearance
• In some individuals, bronchodilators may be harmful, and there is a paradoxical decrease in pulmonary function after bronchodilator use
• Sputum from Inflamed Airways

  Main components are mucins, DNA, and actin
• Mucins


  Protein core, heavily glycosylated with oligosaccharide side chains, disulphide bonds link glycoprotein subunits into macromolecular mucin molecules
• DNA


  Highly negatively charged linear DNA released from chromatin of necrotic neutrophils
• Actin


  Filamentous protein that forms the cytoskeleton of neutrophils, relatively negatively charged
• Mucus viscoelasticity


  Physical entanglements, interactions between charged groups, disulphide bonds, hydrogen-bonding
• Mucolytics


  • Deoxyribonuclease (DNase, Pulmozyme, Dornase alfa)
  • Sulphydryl reagents (dithiothreitol, N-acetyl cysteine)
  • High frequency oscillation
  • Mannitol
  • Hypertonic saline
  • Heparin, dextran sulphate
• Determining if a Microorganism is Pathogenic

  • Acute pulmonary exacerbations of symptoms
  • Development of an antibody response
  • Increasing chest radiographic signs of infection or altered high resolution chest CT images
  • Rapid decline in lung function
  • Increased mortality
• Anti-Pseudomonal Therapy for CF


  • Maintenance therapy with inhaled colistin or aminoglycosides
  • Acute exacerbations require intravenous therapy - penicillins, cephalosporins, aminoglycosides, colistin
• Corticosteroids


  Little evidence that they are beneficial in CF
• NSAIDs


  Ibuprofen inhibits neutrophil accumulation by inhibiting nuclear transcription factors NFκB and AP-1 that induce the synthesis of pro-inflammatory cytokines
• Anti-protease


  Neutrophil elastase is an important target for therapy, therapies based on the natural elastase inhibitors, include recombinant alpha1-antitrypsin and secretory leukocyte protease inhibitor
• Gene Therapy for CF


  • CF would seem an excellent candidate as it is a single-gene defect, therapy can be directly applied to airway epithelial cells, but expression of CFTR is transient and difficult to achieve, mucus is a barrier, vectors may induce an immune response and increase inflammation, clinical trials are ongoing but there is little evidence that gene transfer therapy is imminent
• Modifying the Basic Defect

  1. Activation of mutant CFTR

  2. Altering other ion channels
• CFTR Modulators


  • Potentiators (ivacaftor for G551D gating mutation)
  • Correctors (lumacaftor, tezacaftor, elexacaftor for DF508)
  • Orkambi (ivacaftor plus lumacaftor)
  • Symdeko (ivacaftor plus tezacaftor)
  • Trikafta (ivacaftor, tezacaftor, elexacaftor)