Cystic Fibrosis

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Dr. Maynard's update on Cystic Fibrosis (presented on 12/9/10).

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Cystic Fibrosis

  1. 1. Cystic FibrosisRoy Maynard, M.D.December 9, 2010
  2. 2. Objectives for Cystic Fibrosis• Understand the defect involving the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) in the pathogenesis of lung and pancreatic disease in cystic fibrosis patients.• Describe laboratory testing used to confirm a diagnosis of cystic fibrosis.• Recognize the association between nutritional status and lung function in patients with cystic fibrosis.• Name 3 complications of cystic fibrosis.• Understand the rationale for prescribed treatments for pulmonary exacerbations in patients with cystic fibrosis.
  3. 3. Respiratory Disease in CF• Clinical Pulmonary Manifestations – Chronic cough, often productive – Wheezing – Recurrent pneumonia – Nasal polyps – Chronic sinusitis – CF pathogen colonization
  4. 4. Gastrointestinal Disease in CF• Clinical Gastrointestinal Manifestations – Medonium ileus, DIOS, rectal prolapse – Pancreatic insufficiency, pancreatitis – Cirrhosis, portal hypertension – Speenomegaly – Failure to thrive, malabsorption
  5. 5. Physical Feature of Cystic Fibrosis “Clubbing” of the fingers http://en.wikipedia.org/wiki/File:ClubbingCF.JPG Accessed on 11/10/10
  6. 6. Genetics• Northern European ancestry• Autosomal recessive• Most common lethal genetic disease in Caucasians• 1/3,000 births• 30,000 individuals in USA• Chromosome 7• Currently 1,820 known mutations
  7. 7. Genetics(Autosomal Recessive) www.cfnz.org.nz/about-cystic-fibrosis/ Accessed on 11/10/10
  8. 8. Mutations• Multiple types of mutations – Missense (most common 41%) – Frameshift – Splicing – Nonsense – Deletion• Approximately 80% of mutations accounted for in 24 different mutations
  9. 9. Newborn Screening for CF• Newborn screening in Minnesota since March, 2006• Screened for in all 50 states of the union• IRT/DNA screen (immunoreactive trypsinogen)• High false positive rate• Prenatal screening and carrier screening available
  10. 10. Laboratory• Sweat chloride >60 mEq/liter confirmatory• 40-60 mEq/liter indeterminate• <40 mEq/liter is normal• Other labs – Hypoproteinemia – Decreased calcium levels – Hyponatremia – Increased stool fat
  11. 11. Laboratory Diagnosis• Elevated sweat chloride• Newborn screen• Genetic testing• Malabsorption – 15% pancreatic sufficient – 85% pancreatic insufficient
  12. 12. Cystic Fibrosis Transmembrane Regulator (CFTR)• CF gene encodes a large single chain polypeptide of 1,480 amino acids (ATP-binding cassette proteins)• Embedded in lipid membrane of epithelial cells, sweat glands, pancreas and lungs• Mediates solute transport, mostly the chloride channel
  13. 13. CFTR Proteinhttp://en.wikipedia.org/wiki/File:CFTR.jpg Accessed on 11/10/10
  14. 14. Electrolyte Transport Activities of Submucosal GlandsTaussig-Landau, et al. Pediatric Respiratory Medicine. St. Louis: Mosby, Inc., 1999 Accessed on 11/10/10
  15. 15. Pathophysiology• Altered airway secretions – Periciliary fluid through which cilia beat – Overlying mucus gel phase http://www.medscape.com/viewarticle/463495_4 (Figure 1B) Accessed on 11/10/10
  16. 16. Pathophysiology (continued)• Airway Secretions – Decreased water content – Increased solid content – Higher salt content – Increased submucosal glands and goblet cells and their secretions – Increased amount of dehydrated, viscous secretions that obstruct glands and airways
  17. 17. Pathophysiology (continued)• Dilatation of submucosal glands• Mucus plugging of airways• Hypertrophy and hyperplasia of secretory elements• Chronic infections and inflammation• Chronic bronchiolitis• Squamous metaplasia of respiratory epithelium impacts mucociliary clearance• Bronchiectasis• Loss of functional lung parenchyma
  18. 18. Pathophysiology (continued)• Airway inflammation – Documented to start in the infant lung despite being normal at birth – Increased neutrophils – Increased neutrophil elastase and other cytokines – Imbalance in anti-inflammatory cytokines – Proteolytic enzymes destroy airway tissues contributing to bronchiectasis
  19. 19. Pathophysiology (continued)• Respiratory Tract passengers and pathogens – Pseudomonas aeruginosa – Staphylococcus aureus – Haemophilus influenzae – Aspergillus – Stenotrophomonas maltophilia – Burkholderia cepacia
  20. 20. Percent of Patients with Respiratory Infections (by age) http://www.cff.org/UploadedFiles/research/ClinicalResearch/2008-Patient-Registry-Report.pdf Accessed on 11/10/10
  21. 21. Complications of Cystic Fibrosis • Hemoptysis • Pneumothorax • Respiratory failure • Cor pulmonale • Severe sinus disease/nasal polyps • Nutritional failure • Infertility • Allergic bronchopulmonary aspergillosis
  22. 22. Complications of Cystic Fibrosis (continued)• Cirrhosis with portal hypertension• Pancreatitis• Diabetes• Gallbladder disease• Fibrosing colonopathy• Peptic ulcer disease• Arthropathy/arthritis• Asthma
  23. 23. Routine Management• Quarterly visits CF center with pulmonary function testing and nutritional assessment• Annual labs and chest x-rays• High protein diet• Titration of pancreatic enzymes• Fat soluble vitamin supplementation ADEK• Exercise
  24. 24. Routine Management (continued)• Daily chest physiotherapy – Huff and cough – Flutter valve – Percussive therapy – High frequency chest wall oscillation• Nebulizer treatments – Inhaled steroids – Beta-agonist – Recombinant DNase – Hypertonic saline – Inhaled antibiotics
  25. 25. Main Method of Airway Clearance Therapy (ACT) http://www.cff.org/UploadedFiles/research/ClinicalResearch/2008-Patient-Registry-Report.pdf Accessed on 11/10/10
  26. 26. Routine Management (continued) Hill-Rom Vesthttp://www.hill-rom.co.uk/PageFiles/10597/the_vest_w330.jpg Accessed on 11/10/10
  27. 27. Routine Management (continued)• Anti-inflammatory therapies – Ibuprofen – Zithromax – Systemic steroids
  28. 28. Cystic Fibrosis Exacerbations• Diagnosis – 10% or more decline in pulmonary function testing – Increased sputum production – New infiltrate on CXR – Fever/hypoxia – Weight loss
  29. 29. Cystic Fibrosis Exacerbations (continued)• Hospitalizations• Systemic antibiotics (culture directed)• Increased chest physiotherapy• Sinus surgery• Enhance nutrition• Psychosocial issues• End stage evaluate for lung/liver transplantation
  30. 30. Test Results of Cystic Fibrosis Patient (age 15)
  31. 31. Test Results of Cystic Fibrosis Patient (age 16)
  32. 32. Test Results of Cystic Fibrosis Patient (age 22)
  33. 33. Cystic Fibrosis Exacerbation with Pneumonia
  34. 34. Bronchiectasis
  35. 35. Bronchiectasis
  36. 36. Outcomes• Decline in lung function associated with poorer nutritional status.• Decline in lung function has improved with early diagnosis and new therapies over the past two decades.• Median predicated survival has increased over the past two decades.• Increase in lung transplants in patients with end- stage cystic fibrosis pulmonary disease.
  37. 37. FEV1 Percent Predicted vs. BMI in Adults (20-40 years by gender) http://www.cff.org/UploadedFiles/research/ClinicalResearch/2008-Patient-Registry-Report.pdf Accessed on 11/10/10
  38. 38. Outcomes• Decline in lung function associated with poorer nutritional status.• Decline in lung function has improved with early diagnosis and new therapies over the past two decades.• Median predicated survival has increased over the past two decades.• Increase in lung transplants in patients with end- stage cystic fibrosis pulmonary disease.
  39. 39. Median Percent Predicted FEV1 vs. Age (1990 and 2008) http://www.cff.org/UploadedFiles/research/ClinicalResearch/2008-Patient-Registry-Report.pdf Accessed on 11/10/10
  40. 40. Outcomes• Decline in lung function associated with poorer nutritional status.• Decline in lung function has improved with early diagnosis and new therapies over the past two decades.• Median predicated survival has increased over the past two decades.• Increase in lung transplants in patients with end- stage cystic fibrosis pulmonary disease.
  41. 41. Median Predicted Survivalhttp://www.cff.org/UploadedFiles/research/ClinicalResearch/2008-Patient-Registry-Report.pdf Accessed on 11/10/10
  42. 42. Outcomes• Decline in lung function associated with poorer nutritional status.• Decline in lung function has improved with early diagnosis and new therapies over the past two decades.• Median predicated survival has increased over the past two decades.• Increase in lung transplants in patients with end-stage cystic fibrosis pulmonary disease.
  43. 43. Cystic Fibrosis Lung Transplants (1990 – 2008) http://www.cff.org/UploadedFiles/research/ClinicalResearch/2008-Patient-Registry-Report.pdf Accessed on 11/10/10
  44. 44. Research• Gene therapy• CFTR modulation• Restore airway surface liquid• Mucus alteration• Anti-inflammatory• Anti-infective• Lung transplantation• Nutrition
  45. 45. Conclusion• Cystic fibrosis is the most common lethal genetic disease in Caucasians.• Underlying problem uniquely associated with abnormal CFTR protein function.• Increased viscosity of airway secretions causes progressive loss of lung parenchyma and function.• Improved nutritional status associated with better lung function.• Research has and will continue to provide new therapies and interventions to increase longevity.
  46. 46. Q&AThank you for attending!

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