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1. Author: Richard H. Simon, M.D., 2008-2010
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3. Cystic Fibrosis
 Richard H. Simon
Pulmonary and Critical Care Medicine
Department of Internal Medicine
Fall 2008

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. 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. Schematic Representation of CFTR
Genetic Disorder Research Project Wiki Site

7. Pathophysiology of CF
Disease manifestations
Lungs
?

 Sinuses
CFTR Dysfunction  Pancreas
 Liver
 Bones
 Vas deferens

8. Airway Cross Sectional View
Mucus layer
Pericellular layer
with cilia
Epithelial cell layer
Knowles & Boucher 2002;109:571

9. Required Geometry for Effective
Mucociliary Clearance
Knowles & Boucher 2002;109:571

10. Pathophysiology of CF Lung Disease
Source Undetermined

11. Consequences of CFTR Deficiency on
Airway Clearance
Knowles & Boucher 2002;109:571

12. Pathophysiology of CF Lung Disease
CF Gene Mutation
Ion Transport Abnormalities
Altered Airway
Environment
Inflammation Infection
Tissue
Damage
R. Simon

13. Pathophysiology of CF
Lung Disease
CF Gene Mutation
Recurrent Bronchitis
Bronchiectasis
Chronic Respiratory Source Undetermined
Failure
Death
R. Simons

14. Prevalence of Infections in CF Patients
100
P. aeruginosa
80
60
Percent
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. 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. Diagnostic criteria for cystic fibrosis
Part 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. Diagnostic Criteria for Cystic Fibrosis
Part 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. 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. 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 I507
3849+10kbC → T
R347P
0 10 20 30 40 50 60 70
Frequency, %
CF Genetic Analysis Consortium

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. 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. Acute Exacerbations of
CF 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. Acute Exacerbations of
CF Lung Disease
 Antibiotic treatment
 Oral antibiotics
 If symptoms are mild, and
 Bacteria are susceptible
 Intravenous antibiotics otherwise

24. Management of Chronic Lung Disease
in Cystic Fibrosis

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. Mucolytic Therapy for CF
 DNase
(Pulmozyme ®)
 Chronicuse
improves FEV1
and causes fewer
exacerbations
Fuchs HJ, et al. NEJM 1994;331:637-642

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. 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. 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. 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. Effect of 7% Saline on Frequency of
Pulmonary Exacerbations
Elkins MR et al. N Engl J Med 2006;354:229-240

32. Physiotherapy for CF
 No studies in acute exacerbations
 But standard of care treatment
 Beneficial for chronic management

33. Physiotherapy Options for CF
• Flutter
• Acapella
• PEP
• Vest

34. Supplemental Oxygen
 Use same guidelines as COPD

35. Home Versus Hospital Therapy for
Acute Exacerbation
 Home regimen must duplicate full hospital
program
 IV drugs
 Physiotherapy
 Nutrition
 Et cetera
 Results from small studies showed mixed
results

36. Assisted Ventilation in CF
 Past studies show very poor outcomes
 Non-invasive ventilation being used as a
bridge to lung transplantation

37. Lung Transplantation CF
 Bilateral lung transplantation
 Outcome similar to non-CF
transplantation
 Problems
 Long waiting lists
 Many exclusions
 Living donor transplants

38. Number of CF Patients With Lung
Transplants 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. Median Predicted Survival for Cystic
Fibrosis
35
30
25
Age, yr
20
15
10
5
0
1940 1950 1960 1970 1980 1990 2000
Calendar Year
Source Undetermined

40. New Therapies for CF Under Development –
September 2007
Source Undetermined

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. 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. 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. Additional Source Information
for more information see: http://open.umich.edu/wiki/CitationPolicy
Slide 5: Science, September 1989
Slide 6: Genetic Disorder Research Project Wiki Site, http://runkle-science.wikispaces.com/Cystic+Fibrosis
Slide 8: Knowles & Boucher 2002;109:571
Slide 9: Knowles & Boucher 2002;109:571
Slide 10: Source Undetermined
Slide 11: Knowles & Boucher 2002;109:571
Slide 12: R. Simon
Slide 13: Source Undetermined; R. Simon
Slide 14: Cystic Fibrosis Foundation Patient Registry Data. 2005
Slide 18: Shwachman H, Mahmoodian A. Mod Prob Pediatr 1967;10:158
Slide 19: CF Genetic Analysis Consortium
Slide 25: Ramsey B, et al. NEJM 1999;340:23-30
Slide 26: Fuchs HJ, et al. NEJM 1994;331:637-642
Slide 29: Saiman L, et al. JAMA. 2003;290:1749-56
Slide 30: Elkins MR et al. N Engl J Med 2006;354:229-240
Slide 31: Elkins MR et al. N Engl J Med 2006;354:229-240
Slide 38: Source Undetermined
Slide 39: Source Undetermined
Slide 40: Source Undetermined
Slide 41: Science, September 1989