Cystic Fibrosis
FRACP teaching
October 2007
Mark O’Carroll
Respiratory Physician
Introduction
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Mode of inheritence
Genetic defect
Pathology
Pathophysiology
Clinical features
Diagnosis
Therapy
Survival
Cystic Fibrosis
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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
The CF gene: CFTR
CFTR (7q)
mRNA
CFTR Protein
CFTR Protein in
Cell Membrane
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
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)
Pathology
Normal Airway
CF Airway
Pathophysiology
Molecular biology of CFTR
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There has been considerable debate about
the mechanism by which defective CFTR
impacts on airway physiology and mucociliary
clearance (MCC)
The normal airway surface liquid layer
Pathogenesis
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Soon after birth there is intense neutrophilic
inflammation in the CF lung
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IL8 is the predominant cytokine and sentinel neutrophil
chemo attractant
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IL8 is produced by stimulated epithelial cells,
macrophages and neutrophils
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Various factors stimulate further IL8 production to
sustain neutrophil influx (including IL1, TNF, LPS,
Pseudomonas antigens and neutrophil elastase)
Pathogenesis
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TNF stimulates neutrophil secretory and oxidative
processes
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TNF and IL1 prime neutrophils for a heightened
response to chemo attractants
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Neutrophils then release massive amounts of elastase
and other proteases which overwhelm local host
defenses including 1AT and secretory leukocyte
protease inhibitor (SLPI)
Pathogenesis
Neutrophil breakdown
Large amounts high MW DNA
 viscosity of endobronchial secretions
 mucociliary clearance
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.
Diagnosis of CF
Consensus 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]
CF Foundation Patient Registry 2003
Therapy
Approach to the Management of
CF Lung Disease
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
Macrolides
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Most significant recent advance in CF therapy
• 3 RCTs (n=300 pts) + Cochrane review
• All used azithromycin but probable class effect
• Observed improvements in;
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lung function
hospitalisation rate
intravenous antibiotic use
quality of life
weight
Macrolides
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Mechanism of action uncertain
Potential mechanisms;
 Anti-inflammatory
 Up-regulation of CFTR
 Antibacterial effects
Biofilm formation
Quorum sensing
Bacterial adherence
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Seem to work in patients without PsA infection
Appropriate use remains unclear
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
Study Overview
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Patients with cystic fibrosis have inspissated mucus
that is thought to contribute to the pulmonary
exacerbations characteristic of the disease
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As compared with treatment with normal saline, twicedaily 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
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
Effect of Hypertonic Saline on Lung Function
Elkins, M. et al. N Engl J Med 2006;354:229-240
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
Conclusion
Hypertonic saline preceded by a bronchodilator is an
inexpensive, safe, and effective additional therapy
for patients with cystic fibrosis
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
Fuchs et al. NEJM 1994
Fuchs et al. NEJM 1994
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
NEJM Ramsey et al. 1999; 340 (1): 23
Survival
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.
Improved survival
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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
Impact of FEV1 on survival
Thorax 2001
Impact of nutrition on survival
Thorax 2001