39 th National Conference on Pediatric Health Care March 19-22, 2018 CHICAGO Disclosures The Vision and the Journey of Cystic Fibrosis: Newborn Screening to Breakthrough Therapy March 20, 2018 Cynthia Brady, DNP, CPNP AC The speaker has no financial interests or relationships regarding the subject matter of this presentation to disclose Learning Objectives Describe the basic defect of cystic fibrosis (CF) Interpret results of CF Newborn Screening Program Understand how the Cystic Fibrosis Foundation supports advances in care and life expectancy Recognize how CF centers use CFF registry data to provide and improve care Appreciate breakthroughs in research for CF Woe to the child that tastes salty when kissed on the brow, for he is cursed and will soon die Northern European Folklore What is Cystic Fibrosis? Cystic fibrosis is a progressive, genetic disease that causes persistent lung infections and limits the ability to breathe over time Background Initially identified in 1938 as cystic fibrosis of the pancreas Incidence of 1/~3,500 births in the United States 1/3,200 Caucasian 1/8,000 Latino 1/15,000 African American 1/30,000 Asian 1:30 carrier status in Caucasian Americans 1
Genetics of Cystic Fibrosis CF occurs when a person has two CFTR mutations, one from each parent A child born to two carriers of CF has 25% chance of having CF 50% chance of being a carrier 25% chance of being neither a carrier or having clinical disease Most often in new diagnoses, there is no family history of CF CF Basic Defect Video Video 1 CFTR Mutation Mechanisms of Action How is Cystic Fibrosis Diagnosed? Cystic Fibrosis Infection, Inflammation Blocked ducts, Impaired mucosal defense Altered secretions Ion transport CFTR protein CFTR DNA CF lung disease begins at birth Abnormal CFTR protein and abnormal mucus causes: Obstruction Respiratory tract infection Inflammation Leading to: Structural damage Bronchiectasis Pulmonary insufficiency Eventually causing respiratory failure 1 Clinical Symptoms Chronic, productive cough Excessive sweat, salty taste Failure to thrive or poor weight gain, despite voracious appetite Greasy, foul smelling stools 2 Newborn Screening Pre symptomatic diagnosis In 2016, 624% of total new CF diagnoses and 86% of diagnoses among those less than 6 months old were detected by newborn screening Diagnostic Laboratory Studies CF Diagnosis 1 Quantitative sweat chloride* < 30 meq/l UNLIKELY CF 30 60 meq/l INTERMEDIATE, INCONCLUSIVE > 60 meq/l POSITIVE DIAGNOSTIC FOR CYSTIC FIBROSIS 2 CFTR molecular testing Blood test to identify CFTR mutations What is Newborn Screening? Blood spot more than 50 metabolic, endocrine, blood, pulmonary/digestive, and immune disorders Hearing loss of hearing in the range where speech is heard Pulse oximetry critical congenital heart disease The term PKU test is not accurate and confuses parents! *Infants < 6 months (Farrell et al, Guidelines for Diagnosis of Cystic Fibrosis in the Era of Newborn Screening J Pediatrics 153:S4, 2008) 2
Why Screen for Cystic Fibrosis? 1 Nutrition and Growth Better growth persists into teen years Few cough symptoms, higher FEV 1 and better chest x ray scores at 6 years of age (Lai et al, Pediatrics, 2009;123:714 722) 2 Cognitive Development Vitamin E deficiency correlated with significantly lower memory skills Early nutritional insult associated with stunted cognitive development 3 Survival Decreased number of deaths in patients screened vs nonscreened Prevents fatal protein calorie malnutrition and electrolyte imbalance in infants; saves lives! (Waters et al, 1999), (Farrell et al, 2005) Why Screen for Cystic Fibrosis? 4 Pulmonary Benefit Variable outcomes: Significantly higher FEV 1 in patients diagnosed by newborn screen Adolescents diagnosed via newborn screening normal pulmonary function 5 Early Specialist Care Careful, frequent comprehensive evaluations by a mul disciplinary team Avoidance of complica ons and preven on of lung disease Careful nutri onal management Improve quality of life Why Screen for Cystic Fibrosis? 6 Parents and Family Members Genetic counseling Prevent misunderstandings Reproductive decision making Identification of carrier parents and other family members Identification of other affected family members Viewed as favorable by families: With an infant identified by newborn screening With an infant identified as being a carrier by newborn screening Why Screen for Cystic Fibrosis? 7 Society Cost effectiveness Lower annual cost per newly diagnosed CF infant via newborn screen vs diagnosed CF patient based on clinical symptoms Helps to eliminate disparities associated with access to services Newborn Screening in Minnesota High throughput lab (~70,000 births/year) Birth hospitals record demographics, collect samples, and send specimen cards to the Minnesota Department of Health Screening complete ~1 week Newborn Screening Step One State Newborn Screening Laboratory All specimens analyzed for Immunoreactive Trypsinogen (IRT) Pancreatic enzyme 3
Newborn Screening Step Two State Newborn Screening Laboratory Elevated IRT triggers mutation analysis 2 MUTATIONS: MOST LIKELY CF 1 MUTATION: MOST LIKELY A CARRIER CF Mutation Panel: Newborn Screening Step Three Referral for Sweat Test in an accredited CF center ΔF508 1717 1G>A W1282X 2307insA ΔI507 R560T N1303K Y1092X> G542X R553X 394delTT M1101K G85E G551D Y122X S1255X R117H 1898+1G>A R347H 3876delA 621+1G>T 2184delA V520F 3905insT 711+1G>T 2789+5G>A A559T 1078delT 3120+1G>A S549N 5T/7T/9T S549R R334W R1162X F508C R347P 3659delC 1898+5G>T I507V A455E 3849+10kbC>T 2183AA>G I506V Laboratory Screening Algorithm MN Cystic Fibrosis Data 2015 repeat IRT is elevated IRT values >170 and IRT 96 percentile (based on daily curve that excludes IRT values greater than 170) 0 mutations BORDERLINE mutation analysis Run IRT 1 or 2 mutations repeat IRT is normal POSITIVE IRT < 96 percentile (based on daily curve that excludes IRT values greater than 170) NEGATIVE Positive result reported to Primary Care for referral to accredited CF center for sweat test 53% flagged for 2 nd tier molecular testing 68,490 infants screened 274 infants referred by NBS for sweat testing 239 diagnosed as Carriers 25 diagnosed with CF 10 diagnosed with CRMS MDH was notified of 1 false negative POSITIVE NEGATIVE YOU Can Make a Difference If newborn screen is positive for CF Ensure you have received and reviewed NBS report Make sure you understand the screening result and recommended follow up Call health department or accredited CF center if you don t Be informed of information given to families at time of diagnosis to reinforce recommendations made by CF center Help coordinate necessary follow up appointments Communicate result with the family 4
Critical Times for Parents Being informed of positive screening result Family history CFTR related metabolic syndrome Range of emotions Waiting for sweat test Genetic counseling appointment at the time of sweat test Step 3: Sweat Chloride Testing Necessary to confirm or rule out CF after a positive screening result for CF Should be performed at a CF Center following CFF guidelines May be done when infant is 3 4 weeks old (> 2 kg) Sweat is collected for 30 minutes Sweat chloride concentration is quantified STEP THREE Sweat test and appointment with Genetic counselor Positive Sweat test (>60) Intermediate sweat Test(30 60) Negative Sweat Test (<30) Quantity not sufficient Baby has Cystic Fibrosis May be milder form of CF Baby is most likely a carrier Repeat in 4 weeks Begin CF Care in CF Center Follow up in CF Center Genetic Counseling Cystic Fibrosis: A Patient s Perspective Cystic Fibrosis Foundation The mission of the Cystic Fibrosis Foundation is to cure cystic fibrosis and to provide all people with the disease the opportunity to lead full, productive lives by funding research and drug development, promoting individualized treatment and ensuring access to high quality, specialized care Video 2 cfforg 5
Ensuring access to high quality, specialized care: CF Care Center Accreditation, support for team registry CF Care Model Patient referred to CF Center for initial evaluation Multi disciplinary team concept: CF physician/nurse Practitioner Nurse Coordinator Social worker Dietician Physical therapist/respiratory therapist Genetic counselor Psychologist Pharmacist Research Coordinator Courtesy childrensmnorg Patient Registry National data Data to identify health trends, effective treatments, and potential research opportunities Research Quality Track guidelines Collective data Center data Patient data CF Foundation: Evidence Based Guidelines Panel of multi disciplinary experts Review literature published in peer reviewed journals CF Chronic therapies Pseudomonas Pre school care CFTR modulator drugs Registry Report: All Centers Improving Care for Children with CF 1 Nutrition and Growth Reduce the proportion of children in nutritional failure by increasing use of nutritional status classification Self management goals Appropriate interventions in order to increase BMI percentiles Monitor growth parameters (height, weight, BMI) 2 Lung Function Maintain lung function by diagnosing problems early and treating quickly Monitor lung function with pulmonary function tests (PFTs) including FEV 1 6
Lung Function Improvement Project Adherence to Four Interventions Proven in Large Prospective Trials Pulmozyme, Hypertonic saline and Tobi and Azithromycin in Pseudomonas Positive Patients Registry Report: All Centers FEV 1 vs BMI Statistically significant improvement in prescribing Pulmozyme, hypertonic saline, and Tobi (p=0011) Hypertonic saline and Tobi positively improved mean FEV1 (p=0018 and p=0011) Moderate correlation between improved adherence and improved mean FEV 1 (R=0533) Registry Report: Care Center Children s Hospitals and Clinics Minneapolis, MN * Adjusted for attained age of patients, gender, pancreatic sufficiency, race/ethnicity, socioeconomic status, and age of diagnosis This data was reported to the CF Foundation's Patient Registry January 1, 2013 through December 31, 2013 Individual Registry Report Median Life Expectancy 7
Life Expectancy with Current Treatments cfforg Nutrition Exocrine Pancreatic Insufficiency is the most common GI complication related to CF Thick, sticky mucus obstructs pancreatic ducts and prevents enzymes from reaching gut and digesting food properly Affects approximately 85% of patients Symptoms Steatorrhea Malabsorption/Malnutrition, failure to thrive Fat soluble vitamin deficiencies Treatment Digestive Enzymes Digest carbohydrate, protein, and fat Current Therapies Mucociliary Clearance Video 3 Dornase alpha Placebo rhdnase Category Before After Before After Severity of bronchiectasis 008 ± 029 025 ± 045 017 ± 039 008 ± 029 Peribronchial thickening 042 ± 051 058 ± 067 058 ± 067 038 ± 048 Air trapping 042 ± 067 025 ± 045 050 ± 067 008 ± 029 Infection/Inflammation Patients with CF are more likely to develop bacterial infections due to increased mucus burden (acute or chronic exacerbations) Treatment o Antibiotics Inhaled Aztreonam Tobramycin Oral Cipro, Levofloxacin, Cephalexin, TMP/SMX IV Tobramycin, Ceftazadime, Vancomycin Meropenem Ciprofloxacin, levofloxacin Chronic Azithromycin 8
Advances in Research (Treating the Basic Defect) Video 4 CFTR Gating Mutations CFTR protein is imbedded in epithelial cell membranes and is shaped like a tunnel Gated to allow passage of chloride into/out of the cell Gating mutations prevent the normal movement of chloride into the cell due to defective, closed gate Ivacaftor is a CFTR potentiator that binds to the channel itself, increasing the frequency of gate opening Ivacaftor is approved for use in 33 mutations Video 5 Absolute Change from Baseline Through Wk 48 in Percent Predicted FEV 1 B Ramsey et al NEJM 365:1663 72 (2011) Change from Baseline in Sweat Chloride Levels B Ramsey et al NEJM 365:1663 72 (2011) 9
Personalized Medicine Personalized medicine Based on a patient s mutations Theratyping new FDA process Matching Mutations to CFTR Modulators in the Lab by testing modulator response in a cell CFTR modulators currently approved by the FDA 1 Ivacaftor approved 2012 with clinical trails for 10 mutations 22 more mutation were approved in 2017 with theratyping 2 Lumacaftor/Ivacaftor approved for homozygous ΔF508 mutations Folding Mutations Class II CFTR protein is created, but misfolded, keeping it from reaching the cell surface ΔF508 Lumacaftor + ivacaftor (ORKAMBI ) Approved for use in patients 6yrs + with 2 copies of ΔF508 Lumacaftor helps get more CFTR protein to the cell surface Ivacaftor corrects faulty gate, allowing chloride to flow in/out of the cell Tezacaftor + ivacaftor (Phase 3) Class I mutations CFTR protein is not synthesized More difficult mutation to correct PTC codons Nonsense mutation Terminate translation early 10% of CF cases worldwide Read through agents Gene editing CRISPR/Cas9 Video 6 Co Production of Care Co production of healthcare services is defined as providers, patients and families working together to produce services Shared planning and execution Respectful interactions Effective listening and communication 10
Co Production of CF Healthcare Services Smartphone Application EXPECT DELAYS Many thanks to Cystic Fibrosis Foundation (cfforg) Sondra Rosendahl and the Minnesota Department of Health Children s CF Center Dr Anne Griffiths, Dr Brooke Moore, Dr John McNamara Renee Temme, GC Marisa Eastman, CRCCS Patients and families References CFForg Van Goor F et al Proc Natl Acad Sci USA 2009;106:18825 18830 Accurso FJ et al N Engl J Med 2010;363:1991 2003 Ramsey BW et al N Engl J Med 2011;365:1663 1672 Lahiri T, Hempstead SE, Brady C, et al Clinical Practice Guidelines from the Cystic Fibrosis Foundation for Preschoolers with Cystic Fibrosis Pediatrics 2016;137(4):e20151784 Mogayzel PJ, Naureckas ET, Robinson KA, Brady CJ, Guill M, Lahiri T, et al Cystic Fibrosis Foundation Pulmonary Guideline Pharmacologic Approaches to Prevention and Eradication of Initial Pseudomonas aeruginosa Infection Annals of the American Thoracic Society 201411:10, 1640 1650 Mogayzel,P J et al Brady, C J, Cystic Fibrosis Pulmonary Guidelines: Chronic Medications for Maintenance of Lung Health April 1, 2013, American Journal of Respiratory and Critical Care Medicine Journal Id : Blue 201207 1160OER1 Farrell et al, Guidelines for Diagnosis of Cystic Fibrosis in the Era of Newborn Screening J Pediatrics 153:S4, 2008 Waters et al, 1999 Accurrso et al, 2005 Balfour Lynn, IM, 2008 Collins, MS et al, Pediatric Pulmonology, 2008 Tluczek et al, 2006 Lee et al, 2003 Dillard and Tluckzek J Pediatrics 2005; 147;S94 S97 11