Cystic fibrosis: From childhood to adulthood. Eitan Kerem Department of Pediatrics and CF Center Hadassah University Hospital Jerusalem Israel

Transcription

1 Cystic fibrosis: From childhood to adulthood Eitan Kerem Department of Pediatrics and CF Center Hadassah University Hospital Jerusalem Israel

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3 Vas deference

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7 H 2 O Cl - Na + H 2 O Na + Cl - Cl - Cl - Ca 2+ camp 2Cl K + K + - Na + K + Na +

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15 CFF Patient Registry Annual data report 2005

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17 The 10 golden rules of CF care Maintain good nutrition Daily chest physiotherapy Pharmacological enhancement of mucociliary clearance Avoid pseudomonas infection Early diagnosis and prevention of non-apparent lung damage Early and aggressive antibiotic therapy of respiratory infection Anti-inflammatory therapy Identify and treat complications Centered care Regular and frequent routine evaluation

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19 Causes of malnutrition in CF Pancreatic insufficiency Chronic lung disease Malabsorption fat, micronutrient energy Chronic cough Dyspnea Recurrent infections Vomiting Fatigue Anorexia Increased losses Increased needs Decreased intake Malnutrition

20 The 10 golden rules of CF care Maintain good nutrition Daily chest physiotherapy Pharmacological enhancement of mucociliary clearance Avoid pseudomonas infection Early diagnosis and prevention of non-apparent lung damage Early and aggressive antibiotic therapy of respiratory infection Anti-inflammatory therapy Identify and treat complications Centered care Regular and frequent routine evaluation

21 Physiotherapy Retained purulent secretions have etiologic role in airway disease Variety of techniques: Postural drainage and percussion (CPPT) Percussive vest Airway maneuvers (PEP) Flutter valves / airway occlusion devices (AOD) Aerobic exercise

22 Physiotherapy routinely used: 1-3 times daily Meta analysis 35 studies: PT better than no PT for clearance No long term evidence of therapeutic effect No evidence one technique superior to others

23 The 10 golden rules of CF care Maintain good nutrition Daily chest physiotherapy Pharmacological enhancement of mucociliary clearance Avoid pseudomonas infection Early diagnosis and prevention of non-apparent lung damage Early and aggressive antibiotic therapy of respiratory infection Anti-inflammatory therapy Identify and treat complications Centered care Regular and frequent routine evaluation

24 Inhaled Hypertonic (7%) Saline 7% inhaled BID following albuterol pretx x 48 wks 162 subjects, Age >6, with FEV 1 > 40% 70 ml increase in FEV1 (p>0.05), composite p<0.05 Elkins et al. NEJM, (3):229-40

25 Dornase Alfa in Mild CF Mean change from baseline FEV 1 (% predicted) Week Treatment effect: 3.2% ± 1.2% predicted, *P = * % Free of Exacerbation Dornase alfa Placebo Week RR 0.66 [95% CI ]; P < 0.05 Dornase alfa Placebo Quan JM, et al. J Pediatr, (6):813-

26 The 10 golden rules of CF care Maintain good nutrition Daily chest physiotherapy Pharmacological enhancement of mucociliary clearance Avoid pseudomonas infection Early and aggressive antibiotic therapy of respiratory infection Early diagnosis and prevention of non-apparent lung damage Anti-inflammatory therapy Identify and treat complications Centered care Regular and frequent routine evaluation

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28 Fraction surviving Chronic P aeruginosa colonization Predicts Poor Survival in CF Time (months) *P <0.01 mucoid vs no Pa or nonmucoid Henry RL, et al. Pediatr Pulmonol, 1992; Mar;12(3): * No Pa (n = 12) Nonmucoid Pa (n = 19) Mucoid Pa (n = 50) % of patients without chronic infection Treatment (n = 48) Historical control (n = 43) Months of observation P <0.005 treatment vs control Frederiksen B, et al. Pediatr Pulmonol, 1997; 23:

29 Avoid cross infection!!! Hand washing facilities and alcohol-based hand rubs must be present and used!

30 Patient segregation Fully indicated B. cepaecia MRSA Relatively indicated P. aeruginosa

31 Antibiotic Therapy Guided by culture data Sputum culture (for CF organisms) Recommended frequently (at every clinic visit) + with exacerbations Oral Therapy Criteria: Mild exacerbation Sensitive organism Treat days Staph aureus: doxycycline, macrolide, amox/clavulanate P aeruginosa: FQ +/- inhaled tobramycin or colistin

32 Inpatient Antibiotic Therapy IV Therapy Criteria: Severe exacerbation Resistant bacteria Failed oral therapy Treat days 2 agents based on sputum culture data RCT: PCN + Tobra vs. PCN + Placebo Decreased rate of readmission with Tobra RCT: 3 rd agent offered no additional benefit RCT: culture guided therapy of questionable benefit Multidrug resistance PSA: Synergy studies available Smith AL; et al. Pediatr 1999 Aaron SD et al.lancet 2005 Blumer JL et al. Chest. 2005

33 TOBI: Phase III 520 Patients randomized 300 mg BID nebulized 3 4 week tx periods +10 % vs. 2% change in FEV1 26% reduction in hospitalizations 2 year f/u trial: in adolescents showed similar results: 14.2% relative change in FEV1 Ramsey et al. NEJM 340(1):23-30, 1999 Moss, R. B. Chest 2002;121:55-63

34 Effect of Inhaled Tobramycin on Time to Exacerbation 100 % of patients free of exacerbation Tobramycin Phase III 2 Tobramycin - US Mild CF Study 1 P = Time to first event (weeks) 1 Murphy TD, et al. Pediatr Pulmonol. 38(4):314-20, Ramsey B, et al. NEJM 340(1):23-30, 1999

35 The 10 golden rules of CF care Maintain good nutrition Daily chest physiotherapy Pharmacological enhancement of mucociliary clearance Avoid pseudomonas infection Early and aggressive antibiotic therapy of respiratory infection Early diagnosis and prevention of non-apparent lung damage Anti-inflammatory therapy Identify and treat complications Centered care Regular and frequent routine evaluation

36 Dissociation between structure and function Boy 13 years Lung function FEV 1-99% FVC - 92% FEV 1 /FVC - 90% FEF %

37 10 yrs old, FEV1 86% FVC 93% 13 yrs old, FEV1 96% FVC 91% De Jong et al. ERJ 2004

38 The EarLy Inhaled Tobramycin for Eradication (ELITE) study Ratjen et al. Thorax 2010

39 Proportion of patients free of P. aeruginosa at day 28 and 1 month after the end of treatment Ratjen et al. Thorax 2010

40 Time to recurrence of P. aeruginosa Ratjen et al. Thorax 2010

41 The 10 golden rules of CF care Maintain good nutrition Daily chest physiotherapy Pharmacological enhancement of mucociliary clearance Avoid pseudomonas infection Early diagnosis and prevention of non-apparent lung damage Early and aggressive antibiotic therapy of respiratory infection Anti-inflammatory therapy Identify and treat complications Centered care Regular and frequent routine evaluation

42 Anti-inflammatory inflammatory Therapy: Glucocorticoids Systemic glucocorticoids Inhaled glucocorticoids Ibuprofen Azythromicin

43 Mean Relative Change in FEV1 %Predicted Saiman et al. JAMA 2003;290: Copyright restrictions may apply.

44 Proportion of Patients Remaining Exacerbation-Free Saiman, L. et al. JAMA 2003;290: Copyright restrictions may apply.

45 The 10 golden rules of CF care Maintain good nutrition Daily chest physiotherapy Pharmacological enhancement of mucociliary clearance Avoid pseudomonas infection Early diagnosis and prevention of non-apparent lung damage Early and aggressive antibiotic therapy of respiratory infection Anti-inflammatory therapy Identify and treat complications Centered care Regular and frequent routine evaluation

46 CF Cystic fibrosis in Denmark , 1981, evaluation of centralized treatment Cumulative survival rates in 283 CF patients Nielsen & Schiøtz Acta Paediatr Scand Suppl 1982

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48 The German Cystic Fibrosis Quality Assessment project (CFQA) < 50 patients N=57 >50 patients N=36 < 18 yrs > 18 yrs

49 The best CF centers had more: Routine clinic visits Spirometry tests Sputum cultures Antibiotic therapy

50 The 10 golden rules of CF care Maintain good nutrition Daily chest physiotherapy Pharmacological enhancement of mucociliary clearance Avoid pseudomonas infection Early diagnosis and prevention of non-apparent lung damage Early and aggressive antibiotic therapy of respiratory infection Anti-inflammatory therapy Identify and treat complications Centered care Regular and frequent routine evaluation

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53 CFTR mutations vary in their frequency and distribution in different populations

54 Cystic fibrosis birth rate in Canada Decreasing trend since the onset of genetic testing 1/3608 in /2714 in Dupuiset et al., 2000

55 Number of new cases/year in the USA age of diagnosis < 1 year Provided by Bruce Marshall, NACFF

56 CF rate in North Italy - Veneto/Trentino Incidenza x A significant decrease, ~4/10,000 to ~1.5/10,000 Anno Unpublished results by Castellani.Assael 2009; Castellani, WS18

57 Factors that led to the decrease in CF incidence 1. Carrier testing (pre-conception, prenatal diagnosis) and the option of pregnancy termination 2. Newborn screening resulting in decision of parents: Not to have other children Pre-implantation genetic diagnosis (PGD) Prenatal testing and pregnancy termination

58 CF birth rate in Brittany, France Brittany (1990 to 2005) Scotet et al., J of Pediatr 2008

59 CF birth rate among Ultra Orthodox Jews Culture - arranged marriage (prearranged marriage) Preventing program - obligatory pre-arranged genetic testing?? Bride Groom

60 CF birth rate among Ultra Orthodox Jews ,614 individuals were screened 8,400 carries were identified, (4.4%) 312 potential couples with 1 - in - 4 risk Consequence None of these potential couples married. No more CF births in this population since the initiation of the program Provided by Rabbi Ekstein, Dor Yeshorim

61 Cloning of the CFTR gene - new era in CF research Therapeutic approaches based on CFTR knowledge a. Gene therapy b. Activation of non-cftr chloride channels c. Mutation specific therapies

62 Gene therapy - multidose trial Design 100 CF patients, 50 active v 50 placebo Age months treatment (~ x1/month) Endpoints To be determent from the run-in study Duration Start: beginning of 2011 End end of 2012 Eric Alton, UK;

63 Cloning of the CFTR gene - new era in CF research Therapeutic approaches based on CFTR knowledge a. Gene therapy b. Activation of non-cftr chloride channels c. Mutation specific therapies

64 Identification of Ca 2+ - activated Cl - channels CaCC Cl - epithelial cell Cl - CFTR Ca 2+ -activated Cl - channels (CaCC) are present in the apical membrane of CF and non-cf epithelial cells. Activation of CaCC may compensate the deficit of Cl - transport in CF. Small molecules: Denufosol, Moli-1901 Caputo et al., Science, 2008; Schroeder et al., Cell, 2008; Yang et al., Nature, 2008; Rock et al., 2009

65 Cloning of the CFTR gene - new era in CF research Therapeutic approaches based on CFTR knowledge a. Gene therapy b. Activation of non-cftr Chloride channels c. Mutation specific therapies

66 Classes of CFTR mutations Class III regulation R X R Class II Protein processing Cl - R Class IV Impaired conductance Cl - R Class V Reduced level R Class I No/low synthesis

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71 Building a CF center in Gaza

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73 Thank you!