Cystic fibrosis: From the gene to the disease

Transcription

1 Cystic fibrosis: From the gene to the disease Christiane Knoop, MD, PhD Institut de Mucoviscidose de l ULB Hôpital Erasme christiane.knoop@erasme.ulb.ac.be

2 Cystic fibrosis «The infant that tastes of salt will surely die.» Ancient European saying

3 Cystic fibrosis: milestones 1938 «Cystic fibrosis of the pancreas» = mucous plugs in pancreas of infants dying of malnutrition (Andersen) «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

4 The CFTR gene Tsui, Collins, Riordan Adapted from S Donaldson Plenary Session NACFC

5 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

6 Hypothesized Structure of CFTR Rowe et al. N Engl J Med 2005;352:1992.

7 Cl - MSD = membrane-spanning domain NBD = Nucleotide-binding domain R = Regulatory protein

8 Categories of CFTR Mutations Rowe et al. N Engl J Med 2005;352:1992.

9 10 non-cftr genetic polymorphisms studied, e.g. ACE, α1-antiprotease, IL-10, MBL, NOS, TGFβ, TNFα

10 CF: Incidence Inheritance by simple Mendelian autosomal recessive fashion Incidence in Caucasians 1:3200 African-Americans 1:15000 African-Asians 1:31000 Healthy carrier 1/25

11 CF in Belgium RBM-BMR Draft Report

12 Registre Belge de la Mucoviscidose (RBM-BMR) Annual Data Report 2005

13 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

14 Mechanism Underlying Elevated Sodium Chloride Levels in the Sweat of Patients with Cystic Fibrosis CF sweat duct Rowe S et al. N Engl J Med 2005;352: Rowe et al. N Engl J Med 2005;352:1992.

15 Models Explaining the Transepithelial Potential Difference across the Airway Epithelium in Cystic Fibrosis Rowe et al. N Engl J Med 2005;352:1992. Decreased Cl absorption, decreased NaCl absorption Excessive function of Na channels, non-cftr Cl uptake = relative increase in NaCl absorption, deshydratation

16 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.»

17 Cystic fibrosis: clinical presentation 5th South Eastern European Cystic Fibrosis Conference 17

18 CF Lung disease Broncho-pulmonary disease Bronchiectasis ABPA PNO Massive hemoptysis 5th South Eastern European Cystic Fibrosis Conference

19

20 Pseudomonas aeruginosa: wild and mucoid type

21 Pathogenesis Defective CF gene Defective / Deficient CFTR Decreased Cl secretion Increased Na absorption Bronchial obstruction Infection Inflammation Bronchiectasis Therapeutic approaches Gene therapy Activation of mutant CFTR Protein replacement Rx Cl channel activators Na channel blockers Airway clearance Rx Bronchodilators, Mucolytics Vaccines / Antibiotics AZM Anti-inflammatory agents Lung transplantation Adapted from Davis and Konstan NACFC 2004

22 Respiratory complications Allergic broncho-pulmonary aspergillosis (ABPA) Pneumothorax Hemoptysis 5th South Eastern European Cystic Fibrosis Conference

23 ABPA: Pathogenesis Aspergillus widely distributed fungus Sensitization to inhaled Asp antigens Allergic inflammatory response 5th South Eastern European Cystic Fibrosis Conference

24 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

25 ABPA and CF

26 ABPA: Treatment strategies Oral corticosteroids +/- anti-fungal treatment Itraconazole Voriconazole Alternatives: Steroid pulses Anti-IgE antibodies (Omalizumab) Add-on treatment

27 ABPA and CF

28

29 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:

30 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: th South Eastern European Cystic Fibrosis Conference

31 Pneumothorax: Pleurodesis? First PNO NO Recurrent PNO depends Large ipsilateral YES Small ipsilateral? Preferred method: Surgical pleurodesis: thoracoscopy/tomy 2 nd choice chemical pleurodesis Do not compromise future LTx Flume et al. Am J Respir Crit Care Med 2010; 182:

32 Pneumothorax: Airway clearance techniques PEP and IP percussion to be withheld Flume et al. Am J Respir Crit Care Med 2010; 182:

33 Pneumothorax: Aerosol therapy Flume et al. Am J Respir Crit Care Med 2010; 182:

34

35 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 and chronic inflammation / infection Episodic / recurrent / persistent bleeding into vessel lumen Hemoptysis

36 Minor hemoptysis Contributing causes: Chronic infection Vitamine K deficiency Platelet dysfunction Thrombocytopenia > hypersplenism Adults > children Common > 9% patients in 5-yr interval

37 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

38 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:

39 Hemoptysis: Airway clearance techniques Scant hemorrhage go on Moderate? Massive stop all ACT, clot mobilization? Flume et al. Am J Respir Crit Care Med 2010; 182:

40 Hemoptysis: Aerosol therapy Scant go on Moderate go on Massive: stop hypertonic saline, DNAse? Flume et al. Am J Respir Crit Care Med 2010; 182:

41 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: th South Eastern European Cystic Fibrosis Conference

42

43

44 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

45 CF: Other systems involved Sinus disease Rheumatologic disease Osteoporosis Infertility 5th South Eastern European Cystic Fibrosis Conference

46

47 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 patients,tobi vs placebo, 24 weeks, lung function (adolescents), density of Ps ae, hospitalization Ramsey adolescents, TSI, intermittent, 2 yrs, weight + lung function Moss young CF patients with mild lung disease, TOBI vs placebo, 56 weeks, hospitalization + antibiotic use Murphy 2004 Consensus Clinically effective, very inefficient method of ab delivering, produces high lung concentrations and low serum levels of ab

48 Mean Change in FEV1 in Patients Receiving Inhaled TOBI or Placebo N = 520 Ramsey et al. N Engl J Med 1999;340:23.

49

50

51

52 Other novel inhaled antibiotics SLIT Amikacin (liposomal amikacin) Colistineb Aztreonam lysinate

53 Inhaled antibiotics: Dry powder formulations Tobi Tobramycin DPI Proof of principle (deposition) Safety (?), Doses???, Efficacy???

54 Pathogenesis Defective CF gene Defective / Deficient CFTR Decreased Cl secretion Increased Na absorption Bronchial obstruction Infection Inflammation Therapeutic approaches Gene therapy Activation of mutant CFTR Protein replacement Rx Cl channel activators Na channel blockers Airway clearance Rx Bronchodilators, Mucolytics Antibiotics AZM Anti-inflammatory agents Bronchiectasis Adapted from Davis and Konstan NACFC 2004

55 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 CF patients treated with 500 mg clarithromycin for 6 weeks, idem Ordonez AJRCCM 1999

56 CF and AZI : randomized, placebo-controlled trials 60 adult patients, FEV (± 22.3) %, Azi 250 mg/d vs. placebo, 3 mos LF stable vs % FEV1, iv AB (0.37 vs 1.13 /patient), QoL Wolter et al. Thorax 2002; 57: children, FEV 1 61 % (33-80), Azi mg 3x/wk vs.placebo, 6 mos 2 mois «wash-out» 6 mos cross-over FEV %, oral AB Equi et al. Lancet 2002; 360: patients > 6 yrs, Ps. aeruginosa infection > 1 yr, FEV 1 > 30 % PV 87 patients: Azi mg 3x/wk; 98 patients: placebo, > 5 mo FEV 1, iv AB, weight by 0.7 kg Saiman et al. JAMA 2003; 290: 1749.

57 CF and anti-inflammatory agents LTB4 receptor antagonists

58

59 Anti-inflammatory agents Ibuprofen CFF Registry on clinical use of Ibu, ± 8000 patients, significant in yearly FEV 1 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

60 Pathogenesis Defective CF gene Defective / Deficient CFTR Decreased Cl secretion Increased Na absorption Bronchial obstruction Infection Inflammation Bronchiectasis Therapeutic approaches Gene therapy Activation of mutant CFTR Protein replacement Rx Cl channel activators Na channel blockers Airway clearance Rx Bronchodilators, Mucolytics Antibiotics Anti-inflammatory agents Lung transplantation Adapted from Davis and Konstan NACFC 2004

61

62 Pathology Sinus disease Exocrine pancreatic insufficiency CFRD Novel therapeutic approaches Aerosol devices Microbial pancreatic enzymes Fatty acid supplementation? Islet cell transplantation? Gastro-intestinal disease Liver disease Medical Rx Indications for liver transplantation Joint / Bone disease Fertility / Infertility

63 Stabilize class I mutations mrna Insert normal gene