Your SlideShare is downloading. ×
0
Author: Richard H. Simon, M.D., 2008-2010License: Unless otherwise noted, this material is made available under the terms ...
Citation Key                          for more information see: http://open.umich.edu/wiki/CitationPolicyUse + Share + Ada...
Cystic Fibrosis                Richard H. Simon                 Pulmonary and Critical Care Medicine                 Depa...
Objectives     Understand:         The genetic nature of cystic fibrosis (CF)         The pathophysiology of CF lung di...
Cystic Fibrosis      Inherited disease           Autosomal recessive      Gene cloned in 1989:        CFTR           C...
Schematic Representation of CFTR        Genetic Disorder Research Project Wiki Site
Pathophysiology of CF                        Disease manifestations                                 Lungs                 ...
Airway Cross Sectional View        Mucus layer   Pericellular layer           with cilia Epithelial cell layer            ...
Required Geometry for EffectiveMucociliary Clearance         Knowles & Boucher 2002;109:571
Pathophysiology of CF Lung Disease        Source Undetermined
Consequences of CFTR Deficiency onAirway Clearance   Knowles & Boucher 2002;109:571
Pathophysiology of CF Lung Disease                  CF Gene Mutation            Ion Transport Abnormalities               ...
Pathophysiology of CF Lung DiseaseCF Gene Mutation  Recurrent Bronchitis               Bronchiectasis               Chroni...
Prevalence of Infections in CF Patients          100                                                                      ...
Natural History of CF Lung Infections       Ps. aeruginosa or B. cepacia complex species        persist in the lung     ...
Diagnostic criteria for cystic fibrosisPart 1: Clinical Manifestation of Disease     At   least one of the following:    ...
Diagnostic Criteria for Cystic FibrosisPart 2: Laboratory evidence of CFTR abnormality     At   least one of the followin...
Sweat Test for Diagnosis of CF                               1800                               1500             Controls ...
Use of Genotyping to Diagnose CF  Population Frequency of Specific CFTR Mutations Causing CF          ΔF508          G542X...
Genotyping for CF Diagnosis     Current commercial screening tests          Look for presence of between 25 - 100 mutati...
Genetic Diagnosis of CF    Testsbecoming commercially available    for detecting mutations more broadly        PCR used ...
Acute Exacerbations ofCF Lung Disease     Symptoms          Increased cough with sputum production          Hemoptysis ...
Acute Exacerbations ofCF Lung Disease        Antibiotic    treatment            Oral antibiotics                If symp...
Management of Chronic Lung Diseasein Cystic Fibrosis
Aerosolized Antibiotics    High dose tobramycin     proven for chronic     infection      TOBI® 300 mg in 5 ml bid     e...
Mucolytic Therapy for CF    DNase     (Pulmozyme ®)      Chronicuse     improves FEV1     and causes fewer     exacerbat...
Bronchodilators in CF    Nostudies in acute exacerbations but    routinely given    Chronic           use -- FEV1 improv...
Anti-Inflammatory Treatment in CF    Glucocorticoids        Oral (prednisone)              Preserves lung function, but...
Macrolide Therapy for CF                                       Change in FEV1 (% predicted)                               ...
Nebulized Hypertonic Saline (7%)    Effect on FEV1         Randomized, double-          blind, placebo          controll...
Effect of 7% Saline on Frequency ofPulmonary Exacerbations        Elkins MR et al. N Engl J Med 2006;354:229-240
Physiotherapy for CF      No    studies in acute exacerbations           But standard of care treatment      Beneficial...
Physiotherapy Options for CF• Flutter• Acapella• PEP• Vest
Supplemental Oxygen      Use   same guidelines as COPD
Home Versus Hospital Therapy forAcute Exacerbation   Home regimen must duplicate full hospital   program        IV drugs...
Assisted Ventilation in CF    Past   studies show very poor outcomes    Non-invasive ventilation being used as a    brid...
Lung Transplantation CF         Bilateral   lung transplantation         Outcome similar to non-CF         transplantati...
Number of CF Patients With LungTransplants 1988 - 2005                                    200    Number of Transplant Pati...
Median Predicted Survival for CysticFibrosis           35           30           25Age, yr           20           15      ...
New Therapies for CF Under Development –September 2007 Source Undetermined
Cystic Fibrosis 1989                                                                                                      ...
Cystic Fibrosis Now                                                                                                       ...
References   Simon        RH. Treatment of CF lung disease.   UpToDate, 2008.   DavisP. Cystic Fibrosis Since 1938. Am J...
Additional Source Information                             for more information see: http://open.umich.edu/wiki/CitationPol...
Upcoming SlideShare
Loading in...5
×

09.23.08: Cystic Fibrosis

630

Published on

Slideshow is from the University of Michigan Medical School’s M2 Respiratory sequence

View additional course materials on Open.Michigan:
openmi.ch/med-M2Resp

0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total Views
630
On Slideshare
0
From Embeds
0
Number of Embeds
0
Actions
Shares
0
Downloads
26
Comments
0
Likes
0
Embeds 0
No embeds

No notes for slide

Transcript of "09.23.08: Cystic Fibrosis "

  1. 1. Author: Richard H. Simon, M.D., 2008-2010License: Unless otherwise noted, this material is made available under the terms ofthe the Creative Commons Attribution – Share Alike 3.0 License:http://creativecommons.org/licenses/by-sa/3.0/We have reviewed this material in accordance with U.S. Copyright Law and have tried to maximize your ability to use,share, and adapt it. The citation key on the following slide provides information about how you may share and adapt thismaterial.Copyright holders of content included in this material should contact open.michigan@umich.edu with any questions,corrections, or clarification regarding the use of content.For more information about how to cite these materials visit http://open.umich.edu/education/about/terms-of-use.Any medical information in this material is intended to inform and educate and is not a tool for self-diagnosis or areplacement for medical evaluation, advice, diagnosis or treatment by a healthcare professional. Please speak to yourphysician if you have questions about your medical condition.Viewer discretion is advised: Some medical content is graphic and may not be suitable for all viewers.
  2. 2. Citation Key for more information see: http://open.umich.edu/wiki/CitationPolicyUse + Share + Adapt { Content the copyright holder, author, or law permits you to use, share and adapt. } Public Domain – Government: Works that are produced by the U.S. Government. (17 USC § 105) Public Domain – Expired: Works that are no longer protected due to an expired copyright term. Public Domain – Self Dedicated: Works that a copyright holder has dedicated to the public domain. Creative Commons – Zero Waiver Creative Commons – Attribution License Creative Commons – Attribution Share Alike License Creative Commons – Attribution Noncommercial License Creative Commons – Attribution Noncommercial Share Alike License GNU – Free Documentation LicenseMake Your Own Assessment { Content Open.Michigan believes can be used, shared, and adapted because it is ineligible for copyright. } Public Domain – Ineligible: Works that are ineligible for copyright protection in the U.S. (17 USC § 102(b)) *laws in your jurisdiction may differ { Content Open.Michigan has used under a Fair Use determination. } Fair Use: Use of works that is determined to be Fair consistent with the U.S. Copyright Act. (17 USC § 107) *laws in your jurisdiction may differ Our determination DOES NOT mean that all uses of this 3rd-party content are Fair Uses and we DO NOT guarantee that your use of the content is Fair. To use this content you should do your own independent analysis to determine whether or not your use will be Fair.
  3. 3. Cystic Fibrosis   Richard H. Simon Pulmonary and Critical Care Medicine Department of Internal MedicineFall 2008
  4. 4. Objectives   Understand:   The genetic nature of cystic fibrosis (CF)   The pathophysiology of CF lung disease   Know how to diagnose CF   Learnthe basic approach to treating CF lung disease
  5. 5. Cystic Fibrosis   Inherited disease   Autosomal recessive   Gene cloned in 1989: CFTR   Cystic Fibrosis Transmembrane conduction Regulator   1601 mutations in CFTR known to cause CF   An extensive amount of information is known Science, September 1989 about CFTR
  6. 6. Schematic Representation of CFTR Genetic Disorder Research Project Wiki Site
  7. 7. Pathophysiology of CF Disease manifestations Lungs ?     SinusesCFTR Dysfunction   Pancreas   Liver   Bones   Vas deferens
  8. 8. Airway Cross Sectional View Mucus layer Pericellular layer with cilia Epithelial cell layer Knowles & Boucher 2002;109:571
  9. 9. Required Geometry for EffectiveMucociliary Clearance Knowles & Boucher 2002;109:571
  10. 10. Pathophysiology of CF Lung Disease Source Undetermined
  11. 11. Consequences of CFTR Deficiency onAirway Clearance Knowles & Boucher 2002;109:571
  12. 12. Pathophysiology of CF Lung Disease CF Gene Mutation Ion Transport Abnormalities Altered Airway Environment Inflammation Infection Tissue Damage R. Simon
  13. 13. Pathophysiology of CF Lung DiseaseCF Gene Mutation Recurrent Bronchitis Bronchiectasis Chronic Respiratory Source Undetermined Failure Death R. Simons
  14. 14. Prevalence of Infections in CF Patients 100 P. aeruginosa 80 60Percent S. aureus 40 H. influenza MRSA 20 S. maltophilia B. cepacia 0 0 to 1 2 to 5 6 to 10 11 to 17 18 to 24 25 to 34 35 to 44 45+ Age (years) Cystic Fibrosis Foundation Patient Registry Data. 2005
  15. 15. Natural History of CF Lung Infections   Ps. aeruginosa or B. cepacia complex species persist in the lung   True infection, not colonization   Difficulty in eradicating infection:   Intrinsic antibiotic resistance   Acquired antibiotic resistance   Poor antibiotic penetration into secretions   Alginate produced by mucoid Ps. (biofilms)   CF-related defects in mucosal (but not systemic) defenses
  16. 16. Diagnostic criteria for cystic fibrosisPart 1: Clinical Manifestation of Disease   At least one of the following: 1) One or more clinical manifestations of CF   Meconium ileus   Chronic bronchitis / bronchiectasis   Chronic infection of the paranasal sinuses   Pancreatic insufficiency   Salt loss syndromes   Male infertility due to congenital bilateral absence of the vas deferens 2) Positive newborn screening test 3) History of CF in a sibling
  17. 17. Diagnostic Criteria for Cystic FibrosisPart 2: Laboratory evidence of CFTR abnormality   At least one of the following: 1) Elevated sweat chloride test 2) Identification of a mutation in each CFTR gene known to cause CF 3) In vivo demonstration of characteristic abnormalities in ion transport across nasal epithelium (not widely available)
  18. 18. Sweat Test for Diagnosis of CF 1800 1500 Controls Number of normal controls n=4269 Number of patients with CF 1200 CF 240 n=920 900 180 600 120 300 600 0 0 0 20 40 60 80 100 120 140 160 180 mEq/L Shwachman H, Mahmoodian A. Mod Prob Pediatr 1967;10:158
  19. 19. Use of Genotyping to Diagnose CF Population Frequency of Specific CFTR Mutations Causing CF ΔF508 G542X G551D N1303K   1601 CFTR W1282X mutations known 621+1G → T to cause CF R553X 1717-1G → A   Only 25 R1162X mutations have a R117H frequency > 0.1% Δ I5073849+10kbC → T R347P 0 10 20 30 40 50 60 70 Frequency, % CF Genetic Analysis Consortium
  20. 20. Genotyping for CF Diagnosis   Current commercial screening tests   Look for presence of between 25 - 100 mutations   These will detect a CF allele only ~90% of time   For a group of patients with known CF, genotyping would be diagnostic in only ~81% of patients   ∴ Screening for most common mutations is not as sensitive as sweat testing (98%) to diagnose classic CF
  21. 21. Genetic Diagnosis of CF   Testsbecoming commercially available for detecting mutations more broadly   PCR used to amplify all exons and surrounding splice sites   Heteroduplex formation screening and/or sequencing   Analysis for large deletions and duplications   Cost ~ $2,500
  22. 22. Acute Exacerbations ofCF Lung Disease   Symptoms   Increased cough with sputum production   Hemoptysis   Increased shortness of breath   Fever (not required)   Reduction in FEV1   Worsening infiltrates on chest x-ray (not required)
  23. 23. Acute Exacerbations ofCF Lung Disease   Antibiotic treatment   Oral antibiotics   If symptoms are mild, and   Bacteria are susceptible   Intravenous antibiotics otherwise
  24. 24. Management of Chronic Lung Diseasein Cystic Fibrosis
  25. 25. Aerosolized Antibiotics  High dose tobramycin proven for chronic infection  TOBI® 300 mg in 5 ml bid every other month Ramsey B, et al. NEJM 1999;340:23-30
  26. 26. Mucolytic Therapy for CF  DNase (Pulmozyme ®)  Chronicuse improves FEV1 and causes fewer exacerbations Fuchs HJ, et al. NEJM 1994;331:637-642
  27. 27. Bronchodilators in CF   Nostudies in acute exacerbations but routinely given   Chronic use -- FEV1 improves acutely in some patients   β-adrenergic agonists (e.g. albuterol, salmeterol)   Anticholinergic agents (ipratroprium bromide, tiotroprium)
  28. 28. Anti-Inflammatory Treatment in CF   Glucocorticoids   Oral (prednisone)   Preserves lung function, but too many adverse effects   Inhaled   Used for subgroup of with bronchial hyperreactivity (asthma) symptoms   Ibuprofen   Beneficial for young patients   No evidence for improvement in adults
  29. 29. Macrolide Therapy for CF Change in FEV1 (% predicted) 5 Azithromycin  Azithromycin in CF 4 3   Improved FEV1 2   Fewer exacerbations of 1 CF lung disease 0 -1   Uncertain mechanism -2 Placebo of action -3   Anti-inflammatory? -4   Bacterial toxin or 0 4 8 12 16 20 24 28 biofilm production? Study Week Saiman L, et al. JAMA. 2003;290:1749-56
  30. 30. Nebulized Hypertonic Saline (7%)  Effect on FEV1   Randomized, double- blind, placebo controlled trial   N = 164   Inhalation of 4 ml of 7% vs. 0.9% saline bid for 48 weeks Elkins MR et al. N Engl J Med 2006;354:229-240
  31. 31. Effect of 7% Saline on Frequency ofPulmonary Exacerbations Elkins MR et al. N Engl J Med 2006;354:229-240
  32. 32. Physiotherapy for CF   No studies in acute exacerbations   But standard of care treatment   Beneficial for chronic management
  33. 33. Physiotherapy Options for CF• Flutter• Acapella• PEP• Vest
  34. 34. Supplemental Oxygen   Use same guidelines as COPD
  35. 35. Home Versus Hospital Therapy forAcute Exacerbation   Home regimen must duplicate full hospital program   IV drugs   Physiotherapy   Nutrition   Et cetera   Results from small studies showed mixed results
  36. 36. Assisted Ventilation in CF   Past studies show very poor outcomes   Non-invasive ventilation being used as a bridge to lung transplantation
  37. 37. Lung Transplantation CF   Bilateral lung transplantation   Outcome similar to non-CF transplantation   Problems   Long waiting lists   Many exclusions   Living donor transplants
  38. 38. Number of CF Patients With LungTransplants 1988 - 2005 200 Number of Transplant Patients 178 180 153 161 160 146 137 151 142 135 134 141 140 131 120 104 100 92 80 55 53 60 40 20 13 5 6 0 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 Year Source Undetermined
  39. 39. Median Predicted Survival for CysticFibrosis 35 30 25Age, yr 20 15 10 5 0 1940 1950 1960 1970 1980 1990 2000 Calendar Year Source Undetermined
  40. 40. New Therapies for CF Under Development –September 2007 Source Undetermined
  41. 41. Cystic Fibrosis 1989 Clip of Identification of the Cystic Fibrosis Gene: Chromosome Walking and Jumping from Science, September 1989, removed Science, September 1989
  42. 42. Cystic Fibrosis Now Image of Dan Bessette, the child from the September 1989 cover of Science, a 19 year old college sophomore in 2003
  43. 43. References   Simon RH. Treatment of CF lung disease. UpToDate, 2008.   DavisP. Cystic Fibrosis Since 1938. Am J Respir Crit Care Med 2006;173: 475-482.
  44. 44. Additional Source Information for more information see: http://open.umich.edu/wiki/CitationPolicySlide 5: Science, September 1989Slide 6: Genetic Disorder Research Project Wiki Site, http://runkle-science.wikispaces.com/Cystic+FibrosisSlide 8: Knowles & Boucher 2002;109:571Slide 9: Knowles & Boucher 2002;109:571Slide 10: Source UndeterminedSlide 11: Knowles & Boucher 2002;109:571Slide 12: R. SimonSlide 13: Source Undetermined; R. SimonSlide 14: Cystic Fibrosis Foundation Patient Registry Data. 2005Slide 18: Shwachman H, Mahmoodian A. Mod Prob Pediatr 1967;10:158Slide 19: CF Genetic Analysis ConsortiumSlide 25: Ramsey B, et al. NEJM 1999;340:23-30Slide 26: Fuchs HJ, et al. NEJM 1994;331:637-642Slide 29: Saiman L, et al. JAMA. 2003;290:1749-56Slide 30: Elkins MR et al. N Engl J Med 2006;354:229-240Slide 31: Elkins MR et al. N Engl J Med 2006;354:229-240Slide 38: Source UndeterminedSlide 39: Source UndeterminedSlide 40: Source UndeterminedSlide 41: Science, September 1989
  1. A particular slide catching your eye?

    Clipping is a handy way to collect important slides you want to go back to later.

×