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Cystic fibrosis: From the gene to the disease
Christiane Knoop, MD, PhDInstitut de Mucoviscidose de l’ULB –
Hôpital Erasme
Cystic fibrosis
« The infant that tastes of salt will surely die. »
Ancient European saying
Cystic fibrosis: milestones
•1938 « Cystic fibrosis of the pancreas » = mucous plugs in
pancreas of infants dying of malnutrition (Andersen)
•‘40-50 « Mucoviscidosis » = failure to thrive, pulmonary
disease and histological thick inspissated mucous in ≠glands
•1948 Discovery of the basic physiologic defect (di
Sant’Agnese, New York heat wave)
•1983 Identification of the fundamental defect,
the defective chloride transport (Quinton)
•1985 Localization of CF defect on chromosome 7 (Tsui)
•1989 Identification of the gene …
The CFTR gene
4Adapted from S Donaldson Plenary Session NACFC 2013
Tsui, Collins, Riordan
CF: the basic defect
… which encodes for a protein, the
Cystic Fibrosis Transmembrane Conductance Regulator (CFTR),
- a c-AMP regulated chloride channel
- a regulatory protein for other
conductances
Rowe et al. N Engl J Med 2005;352:1992.
Hypothesized Structure of CFTR
MSD =membrane-spanningdomain
NBD = Nucleotide-bindingdomain
R = Regulatory protein
Cl-
Rowe et al. N Engl J Med 2005;352:1992.
Categories of CFTR Mutations
10 non-CFTR genetic polymorphismsstudied, e.g. ACE, αααα1-antiprotease,IL-10, MBL, NOS, TGFββββ, TNFαααα
CF: Incidence
• Inheritance by simple Mendelianautosomal recessive fashion
• Incidence in – Caucasians 1:3200– African-Americans 1:15000– African-Asians 1:31000
• Healthy carrier 1/25
CF in Belgium
11RBM-BMR Draft Report 2011
Registre Belge de la Mucoviscidose (RBM-BMR) – Annual Data Report 2005
CF: Diagnosis
• Evidence of Cl- channel dysfunction (sweat Cl-
≥ 60 mEq/L or NPD consistent with CF)
+• Family history of CF or
• Sino-pulmonary disease or
• Evidence of pancreatic insufficiency
• Genotyping http://www.genet.sickkids.on.ca
Rowe S et al. N Engl J Med 2005;352:1992-2001
Mechanism Underlying Elevated Sodium Chloride Levels in the Sweat of Patients with Cystic Fibrosis
Rowe et al. N Engl J Med 2005;352:1992.
CF sweat duct
Rowe et al. N Engl J Med 2005;352:1992.
Models Explaining the Transepithelial Potential Difference across the Airway Epithelium in Cystic Fibrosis
Excessive function of Na channels, non-CFTR Cl uptake = relative increase in NaCl absorption, deshydratation
Decreased Cl absorption, decreased NaCl absorption
Cystic fibrosis
« There is widespread agreement that defects in ion transport, salt
homeostasis, or both are intimately linked to organ damage in CF.
The precise molecular basis for this connection, however, is unknown. »
Cystic fibrosis: clinical presentation
175th South Eastern European Cystic Fibrosis Conference
CF Lung disease
•Broncho-pulmonary disease
– Bronchiectasis
– ABPA– PNO– Massive hemoptysis
5th South Eastern European Cystic Fibrosis Conference
Pseudomonas aeruginosa: wild and mucoid type
Pathogenesis
Defective CF gene
Defective / Deficient CFTR
Decreased Cl secretionIncreased Na absorption
Bronchial obstruction
Infection
Inflammation
Bronchiectasis
Therapeutic approaches
Gene therapy
Activation of mutant CFTRProtein replacement Rx
Cl channel activatorsNa channel blockers
Airway clearance RxBronchodilators, Mucolytics
Vaccines / AntibioticsAZM
Anti-inflammatory agents
Lung transplantation
Adapted from Davis and Konstan NACFC 2004
Respiratory complications
� Allergic broncho-pulmonary
aspergillosis (ABPA)
� Pneumothorax
� Hemoptysis
5th South Eastern European Cystic Fibrosis Conference
ABPA: Pathogenesis
� Aspergillus widely distributed fungus
� Sensitization to inhaled Asp antigens
� Allergic inflammatory response
5th South Eastern European Cystic Fibrosis Conference
ABPA: Diagnosis
1. Asthma
2. New pulmonary infiltrates
3. Immediate skin reactivity to Asp ag
4. Total IgE > 417 IU/ml
5. Serum ↓↓↓↓ ab against Asp
6. Central bronchiectasis
7. Peripheral blood eosinophilia
8. Elevated IgE/IgG against AF
5th South Eastern European Cystic Fibrosis Conference
ABPA and CF
ABPA: Treatment strategies
� Oral corticosteroids
+/- anti-fungal treatment• Itraconazole
• Voriconazole
� Alternatives:• Steroid pulses
� Anti-IgE antibodies (Omalizumab)• Add-on treatment
ABPA and CF
Pneumothorax: Hospital admission ?
� Small PNO may be observed in the out-patient setting
- asympytomatic- symptomatic ?
� Large PNO = admission
Flume et al. Am J Respir Crit Care Med 2010; 182: 298-306
Pneumothorax: Chest tube ?
� Large PNO – Unstable YES
– Stable YES
� Small PNO – Unstable YES
– Stable NO
Flume et al. Am J Respir Crit Care Med 2010; 182: 298-306
5th South Eastern European Cystic Fibrosis Conference
Pneumothorax: Pleurodesis ?
� First PNO NO
� Recurrent PNO depends– Large ipsilateral YES
– Small ipsilateral ?
� Preferred method: • Surgical pleurodesis: thoracoscopy/tomy
• 2nd choice chemical pleurodesis
• Do not compromise future LTx
Flume et al. Am J Respir Crit Care Med 2010; 182: 298-306
Pneumothorax: Airway clearance techniques
PEP and IP percussion to be withheldFlume et al. Am J Respir Crit Care Med 2010; 182: 298-306
Pneumothorax: Aerosol therapy
Flume et al. Am J Respir Crit Care Med 2010; 182: 298-306
Hemoptysis: Pathogenesis (Hypothesis !)
� Persistent airway inflammation � Angiogenesis →→→→ dilatation of bronchial arteries� Systemic pressure � Proximity of bronchi and bronchiectasies � Damage to vessel walls by acute, recurrent andchronic inflammation / infection
� Episodic / recurrent / persistent bleeding intovessel lumen
� Hemoptysis
Minor hemoptysis
� Contributing causes:• Chronic infection
• Vitamine K deficiency
• Platelet dysfunction
• Thrombocytopenia > hypersplenism
� Adults > children
� Common
� > 9% patients in 5-yr interval
Massive hemoptysis
� > 250 ml / 24 h � Causes:
• Structural anomalies of the bronchi and lung• Chronic infection• Vitamine K deficiency• Platelet dysfunction• Thrombocytopenia > hypersplenism
� Adults > children � Average annual incidence 0.85%� 1/115 CF patients per year� 4.1% patients in their lifetime
Hemoptysis: Management
� Contact doctor ?• Scant < 5 ml ?, 1st episode ever
• Mild > 5 ml Yes
• Massive Absolutely
� Hospital admission ?• Scant No (?)
• …
• Massive Absolutely
Flume et al. Am J Respir Crit Care Med 2010; 182: 298-306
Hemoptysis: Airway clearance techniques
Scant hemorrhage go onModerate ?Massive stop all ACT, clot mobilization ?Flume et al. Am J Respir Crit Care Med 2010; 182: 298-306
Hemoptysis: Aerosol therapy
Scant go onModerate go onMassive: stop hypertonic saline, DNAse ?Flume et al. Am J Respir Crit Care Med 2010; 182: 298-306
Hemoptysis: Bronchial artery embolization ?
� Massive, unstable: Yes
� Massive and stable: ?
� Bronchoscopy before BAE: NO
� Embolize bleeding vessel or all
abnormal vessels: ?
Flume et al. Am J Respir Crit Care Med 2010; 182: 298-306
5th South Eastern European Cystic Fibrosis Conference
CF digestive disease
• Pancreatic disease– Exocrine pancreatic insufficiency– Diabetes– Pancreatic cysts (+ cancer)
• Gastro-intestinal disease– Reflux, gastroparesis– Meconium ileus, DIOS– Digestive infections– Digestive cancers
5th South Eastern European Cystic Fibrosis Conference
CF: Other systems involved
• Sinus disease
• Rheumatologic disease
• Osteoporosis
• Infertility
•…
5th South Eastern European Cystic Fibrosis Conference
Inhaled antibiotics: the evidence
• Meta-analysis of 16 randomized, controlled trials• most studies show ↑↑↑↑ lung function or ↓↓↓↓ decline in active Rx groups • some report ↓↓↓↓ hospital admissions, ↓↓↓↓ Ps ae density
Mukhopadhyay Thorax 1996
Ryan Cochrane Database Syst Rev 2003
• 520 patients,TOBI vs placebo, 24 weeks, ↑↑↑↑ lung function (adolescents),↓↓↓↓ density of Ps ae, ↓↓↓↓ hospitalization Ramsey 1999
• 128 adolescents, TSI, intermittent, 2 yrs, ↑↑↑↑ weight + lung functionMoss 2002
• 400 young CF patients with mild lung disease, TOBI vs placebo, 56 weeks, ↓↓↓↓ hospitalization + antibiotic use Murphy 2004
ConsensusClinically effective, very inefficient method of ab delivering, produces
high lung concentrations and low serum levels of ab
Ramsey et al. N Engl J Med 1999;340:23.
Mean Change in FEV1 in Patients Receiving Inhaled TOBI or Placebo
N = 520
• SLIT Amikacin (liposomal amikacin)
• Colistineb
• Aztreonam lysinate
Other novel inhaled antibiotics
Inhaled antibiotics: Dry powder formulations
Tobi Tobramycin DPIProof of principle (deposition)Safety (?), Doses ???, Efficacy ???
Pathogenesis
Defective CF gene
Defective / Deficient CFTR
Decreased Cl secretionIncreased Na absorption
Bronchial obstruction
Infection
Inflammation
Bronchiectasis
Therapeutic approaches
Gene therapy
Activation of mutant CFTRProtein replacement Rx
Cl channel activatorsNa channel blockers
Airway clearance RxBronchodilators, Mucolytics
AntibioticsAZM
Anti-inflammatory agents
Adapted from Davis and Konstan NACFC 2004
Macrolide Therapy for CF: the beginning
• Erythromycin therapy in a 16-year-old
Japanese CF patient with CF resulted in
improved pulmonary function Nakanisi Nippon Kyobu Shikkan Gakkai Zasshi. 1995
• 7 CF patients treated with 500 mg clarithromycin for 6 weeks, idem
Ordonez AJRCCM 1999
CF and AZI : randomized, placebo-controlled trials
� 60 adult patients, FEV1 56.6 (±±±± 22.3) %, Azi 250 mg/d vs. placebo, 3
mos
� LF stable vs. - 3.62 % FEV1, ↓↓↓↓ iv AB (0.37 vs 1.13 /patient), ↑↑↑↑ QoL
Wolter et al. Thorax 2002; 57: 212.
� 41 children, FEV1 61 % (33 - 80), Azi 250 - 500 mg 3x/wk vs.placebo,
6 mos →→→→ 2 mois « wash-out » →→→→ 6 mos cross-over
� FEV1 + 5.4 %, ↓↓↓↓ oral AB
Equi et al. Lancet 2002; 360: 978.
� 185 patients > 6 yrs, Ps. aeruginosa infection > 1 yr, FEV1 > 30 % PV
� 87 patients: Azi 250 - 500 mg 3x/wk; 98 patients: placebo, > 5 mo
� ↑↑↑↑FEV1, ↓↓↓↓ iv AB, ↑↑↑↑ weight by 0.7 kg
Saiman et al. JAMA 2003; 290: 1749.
LTB4 receptor antagonists…
CF and anti-inflammatory agents
Anti-inflammatory agents
Ibuprofen• CFF Registry on clinical use of Ibu, ±±±± 8000 patients,significant ↓↓↓↓ in yearly FEV1 decline
Schluchter 2004
LTB4 receptor antagonist = BIIL 284 BS• Early termination of study
Statins• Simvastatin once daily, 28 days• Outcome measures: exhaled biomarkers, inflammatory• markers in nasal epithelial cells / induced sputum, • not yet published
Pathogenesis
Defective CF gene
Defective / Deficient CFTR
Decreased Cl secretionIncreased Na absorption
Bronchial obstruction
Infection
Inflammation
Bronchiectasis
Therapeutic approaches
Gene therapy
Activation of mutant CFTRProtein replacement Rx
Cl channel activatorsNa channel blockers
Airway clearance RxBronchodilators, Mucolytics
Antibiotics
Anti-inflammatory agents
Lung transplantation
Adapted from Davis and Konstan NACFC 2004
Pathology
Sinus disease
Exocrine pancreaticinsufficiency
CFRD
Gastro-intestinal disease
Liver disease
Joint / Bone disease
Fertility / Infertility
Novel therapeutic approaches
Aerosol devices
Microbial pancreatic enzymesFatty acid supplementation ?
Islet cell transplantation ?
Medical RxIndications for liver transplantation
Insert normal
gene
Stabilize class I
mutations mRNA