Pediatrics Grand Rounds 18 Sept University of Texas Health Science Center. + Disclosure. + Learning Objectives.

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1 Disclosure Dr Donna Willey Courand receives research support from Cystic Fibrosis Therapeutics The Cystic Fibrosis Foundation Children with Special Health Care Needs Cystic Fibrosis 05: Improving Survival Through Optimization of Care and Innovative Therapeutics Dr Donna Beth Willey-Courand UTHSCSA CF Center Learning Objectives Some CF Basics At the end of this presentation the participant will be able to discuss the impact of Newborn screening Quality Improvement 3 New therapeutic technologies on the survival of patients with cystic fibrosis Autosomal recessive disease Chromosome 7 Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Membrane spanning channel Facilitates movement of Cl and HCO 3 across the cell membrane Ears, sinuses, respiratory tract, pancreas, intestines, liver, kidneys, reproductive tract, sweat glands Diagnosis based on sweat testing, nasal potential difference measurement, genetic testing, clinical stigmata CF In the Gut: Clinical Manifestations Poorly hydrated secretions in the pancreas The Pulmonary Manifestations of CF Obstruction Inflammation Progressive Bronchiectasis/Fibrosis Infection MSSA, MRSA Pseudomonas Fungus Viruses Obstruction of pancreatic ducts Impaired secretion of pancreatic enzymes Malabsortion of fats, proteins, vitamins A,D,E, K Autodigestion of the pancreas Impaired islet cell function Impaired insulin secretion Poorly hydrated intestinal secretions Meconium ileus Constipation Distal Intestinal obstruction syndrome (DIOS)

2 Newborn Screening The median predicted age of survival has increased from 334 years in 003 to 407years in North American Cystic Fibrosis Patient Registry 6% of new CF diagnoses in 03 resulted from newborn screening 03 North American Cystic Fibrosis Patient Registry History of Newborn Screening for CF Wisconsin Randomized clinical trial of NBS Screening based on trypsinogen levels () and F508 Results for controls blinded until 4 years of age Significantly earlier diagnosis ( vs 7 weeks) Improved height, weight, FOC %le at time of dx Better cognitive testing scores? Vitamin E supplementation 004 CDC recommends CF NBS December 009 Texas begins NBS Texas // DNA NBS Algorithm Normal st NB screen Normal Elevated nd NB Screen Normal CF screen Elevated mutations st screen with elevated, nd screen not received after month CFTR mutation analysis mutation 0 mutations Sweat Test Improved Nutritional Outcomes NEJM 997; 337: North American Cystic Fibrosis Patient Registry

3 Impact on Infection Benefits Extend Into Adulthood NBS NBS Control Control Arch Dis Child 0;96:8 3 Arch Dis Child 0;96:8 3 Opportunities to Better Understand Disease Progression/Development Opportunities for Better Survival NBS AREST CF CT and BAL evaluation at 3 months,, and 3 years Bronchiectasis 9% by 3 months 6% by 3 years % increase FEV% associated with 3% decrease in risk of death Each 0 kg/m increase in BMI contributed to 44% decrease in risk of death Screened Not Screened NEJM 03; 368: Arch Dis Child 0;96:8 3 J Pediatr 005; 47:S57-S63 CF Quality Improvement History 003 NICHQ study Publication of center data Funding for participation QI curriculum Dartmouth Microsystem Dartmouth Improvement Ramp Meeting Skills Measurement Coaches The Dartmouth Microsystem Improvement Ramp Cause & Effect Assessment Theme Global Aim Specific Aim Change Ideas Measures Flowchart PDSA A S P D A S P D 3 3 A S P D Global Aim 8 SDSA * 5P Assessment/Effective Meeting Skills Dartmouth Microsystems 3

4 Adj_Rate center Pediatrics Grand Rounds CFF Initiatives Learning and Leadership Collaboratives Nutrition Pulmonary Function Adherence to national guidelines Clinic encounters Screening for diabetes Implementation of infection control guidelines The impact of re-education of airway clearance techniques (REACT)on adherence and pulmonary function in patients with cystic fibrosis QI team of providers and patient families Adherence survey Visualization of administration of therapies Re education on techniques Monitor outcomes BMJ Qual Saf 04: 3: i50-i55 QI at UTHSCSA CF Center Here s where we are now! 003 NICHQ Series of face to face meetings to teach the basics of PDSA cycles and QI What did we do? Nutritional status classified on every visit Nutrition expectations clearly delineated to patients Patients aggressively followed Culture of good nutrition Web based data entry system to track outcomes/run charts Outcomes tracked annually through CF Registry data 4 prevalence 0 4 Prevalence of nutritional failure by center 003 CSRCH CSRCH Current QI Collaboratives The FUN LLC OneCF (I and II) Concept of pediatric and adult programs as one CF Center Focus on transition FunLLC This is good This is not Theme: Understanding and improving the care and management of the pulmonary manifestations of cystic fibrosis Global Aim Statement: We aim to improve the treatment of Pseudomonas aeruginosa infections in the UTHSCSA CF Center 4

5 New Therapies Up until 0, all of the therapies we had fought the symptoms of the disease, but not the cause of the disease Class IV-Reduced Conductance (R7H) Class III-Regulatory Block (G55D)* -Disordered regulation/gating Class II-Altered folding and regulatory block (F508)* -Premature Degradation Class V-Reduced Synthesis* -Promotor/Splice abnormality Class VI-Accelerated Turnover Class I-No Synthesis* -Premature Termination Codons Lukacs, NEJM 003,349: High Throughput Screening Screening for pharmacologic agents that Increase protein kinase A regulated chloride channel gating of CFTR Potentiators: Increase the flow of chloride and bicarbonate through the activated CFTR (Kalydeco) Small molecules that chaperone / rescue misfolded CFTR Correctors: Improve the processing of CFTR and delivery of CFTR to the cell surface (Lumacaftor) Potentiators: Kalydeco (Ivacaftor/VX770) 06% 6 patients > years VX mg twice a day or placebo for 48 weeks in pts with G55D VX770 in 6- year olds % 5 patients 6- years old with G55D FEV 40-05% Body weight > 5 kg 50 mg VX770 twice a day vs placebo for 48 weeks 7 kg 8kg 55% less likely to have pulmonary exacerbation NEJM 0; 365:663-7 AMJRCCM 03;87:9-5 5

6 Further evidence of beneficial effects Kalydeco for other mutations GOAL Study (53 pts, >6yrs, 6 months of use) Sustained FEV* Weight and BMI Sweat Chloride Rate of Hospitaliza on, Rate of Pseudomonas culture Prevotella cultures intes nal ph European CF Conference 6/ 6/4/4 In pa ents > 6 years, decreased rate of lung decline by 50% over 3 years (08% /year vs 73%) Approved for several other gating mutations G55D, G55S G44E, G349D, G78R, S5N, S55P, S549N, S549R Class IV mutation: R7H 50 mg tablets BID (> 6 years of age) 50 mg and 75 mg granules BID( 6 years of age) Examination for cataracts and monitoring liver function recommended Class Mutations- F508 Attempts to Correct F508 48% patients in US F508 x, 40% with F508x NBD misfolding=degredation in ER NBD MSD binding facilitated by F508=key to opening anion channel Little protein reaches the cell membrane and even less of it works! Potentiators: Kalydeco alone Correctors: Lumacaftor -Stabilization of NBD-MSD assembly FDAgov VX770 (Ivacaftor) VX809 (Lumacaftor) CFTR folding-traffic and TRANSPORT Phase 3 studies 08 pts, > years, F508 x 600mg once a day or 400 mg twice a day VX mg VX770 vs placebo 4 weeks with 96 week extension Mean baseline FEV 6% 4-4% FEV >5% >0% Lumacaftor /Ivacaftor 36-46% 4-7% Placebo % 3% NEJM 05; 373(33) 0-3 NEJM 05; 373(33) 0-3 6

7 Lumacaftor Ivacaftor=ORKAMBI TM Approved by FDA 7/3/5 Dosing: Lumacaftor 400 mg/ivacaftor 50 mg twice a day Pts > years of age with F508x Most common side effects Chest tightness, respiratory dyscomfort Elevated liver function? GI disturbances VX66VX770-The Next Generation March 05: week Phase study 39 people >8 years, F508 x VX66 (various doses) VX770 or placebo x8 days VX66(00 mg) VX770 (50 mg) BID 44 % and 3% FEV 38% with pulmonary exacerbation vs 44% placebo 33% with cough vs 39% placebo 4 Phase 3 studies: VX 66 VX770: F508 x (550 pts) F508 gating(00 pts) (4/5) F508 residual function( 300 pts) (5/5) F508 minimal function mutation (0 pts) (Mid 05) Class Mutations Need correctors that help to read through the stop codon to allow for full gene synthesis PTC 4 (Ataluren) Promotes ribosomal read through of premature stop codons/production of full length CFTR Early studies showed improvement in nasal potential difference PTC 4-Ataluren Phase 3 study: 38 patients >6 years with nonsense mutation Ataluren TID(0 mg/kg, 0 mg/kg, 0 mg/kg) x 48 weeks No change in BMI, sweat chloride, or reduction in pulmonary exacerbations AE: Elevated creatinine Lancet Respir Med 04 July ; (7): The Issue of Drug Interactions Readthrough activity of ataluren decreased with co exposure to aminoglycosides Ataluren has no effect on antibacterial activity of tobramycin Study patients not on inhaled tobramycin 57% increase in lung function 40% decrease in exacerbations A look towards the future X Lancet Respir Med 04 July ; (7):