Cystic Fibrosis - Robert Wood Johnson Medical...
Transcript of Cystic Fibrosis - Robert Wood Johnson Medical...
CYSTIC FIBROSIS: Overview and Update
Thomas F. Scanlin MDDepartment of Pediatrics
Pulmonary Medicine and CF CenterBMSCH @ RWJUHRWJMS - UMDNJ
Cystic Fibrosis
• Exocrine gland dysfunction• Classical clinical features
– Chronic lung disease– Pancreatic insufficiency– Elevated sweat chloride
• Autosomal recessive: 1 in 3300 Caucasian births• CFTR Gene and mutations identified• Function of CFTR glycoprotein being defined
Cystic Fibrosis
• Most common fatal genetic disease in U.S. Caucasians
• Affects 35,000 children and adults in the U.S. and 70,000 individuals worldwide
• 1,000 new cases diagnosed every year
Cystic Fibrosis
Ethnicity Incidence CarriersCaucasian 1/3300 1/29Latino 1/6,000 1/39African American 1/10,000 1/50Native American 1/11,200 1/53Asian 1/32,100 1/90
Diagnosis of CF
Adapted from Rosenstein BJ, et al. J Pediatr. 1998.
CF diagnosis can be established if a patient has:
One of these: PLUS one of these:>1 typical phenotypic features of CF
Sweat chloride conc. > 60 meq/l
Sibling with CF 2 identified CFTR mutations
Positive newborn screening test
Abnormal nasal potential difference
Diagnosis Clinical Features
• Chronic sino-pulmonary disease• Gastrointestional / nutritional abnormalities• Obstructive azoospermia in males• Salt-loss syndromes• CF in a first -degree relative
» List is not limited to the above
Pulmonary Signs of CF
• Recurrent pneumonia• Atypical asthma• Pseudomonas in respiratory secretions• Digital clubbing• Bronchiectasis • Nasal polyps in childhood
Immediate benefits from identifying the CF genetic defect
as mutations in CFTR
• Molecular basis for prenatal diagnosis and genetic counseling
• Model for designing specific, rather than symptomatic therapy
N
NBD2
C
RNBD1
BUT…
• Over 1500 mutations have been described in CF
• CF newborn testing is only a SCREEN
• Prenatal tests for CF often include testing for only 23 mutations
CF Newborn Screen in NJIRT
+-
Repeat IRT
+-
CF Center Sweat Test
∆F 5080,1,2 Copies
Pathophysiology of CF
• Defective Gene• Defective /Deficient CFTR• Abnormal Airway Surface Environment• Infection• Inflammation• Bronchial Obstruction• Bronchiectasis
Normal Lung CF Lung
Therapeutic Modalities CF Center-Comprehensive Care
• Chest physiotherapy• Antibiotics• Inhaled Medications
– Mucolytic– Bronchodilator– Anti-inflammatory– Antibiotic
• Pancreatic enzyme replacement
• Nutrition• Psychosocial support
Survival Age in CF by Year
Data from Cystic Fibrosis Foundation
Airway Clearance Techniques
• Percussion & Postural Drainage• Positive Expiratory pressure• Active Cycle of Breathing Technique• Autogenic Drainage• Oscillating PEP Devices• High Frequency Chest Compression• Exercise
ESCF
Patients with lower Weight for Age or
Height for Age at age 3 have lower FEV1 at age 6
There is a wide variation in outcomes in different CF Centers
• “ The Bell Curve” by Atul Gawande.
• The New Yorker, December, 2004
Chloride conductance and genetic background modulate the cystic
fibrosis phenotype of ΔF508 homozygous twins and siblings
J. Clin. Invest. 108 (11): 1705-1715 (2001).
0.9
0.8
0.7
0.6
CumulativeSurvival
1.0 Late acquisition (> 6 yrs)
Early acquisition (< 6 yrs)
malesfemales
6 8 10 12 14 16Age (yr)
Demko et al, J Clin Epidemiol 1995; 48:1041
p < 0.001
Prognostic Value of Early Prognostic Value of Early P. aeruginosaP. aeruginosa InfectionInfection
CFF Infection Control Guidelines for Performance of Airway
Clearance
• Gown• Glove • Mask • Eye Protection
PFTs in CF Pulmonary Exacerbation
FVC FEV1 RV/TLC SGAW SpO2
Baseline 70-80
Admit -- -- -- -- --
Week #1 47 19 241 39 93
Week #2 66 32 172 51 97
Week #3 85 39 147 57 98
Week #4 91 47 151 97 98
Predicted Mortality
When FEV1 remains less than 30% predicted, despite
aggressive treatment, there is approximately a 50% mortality
in 2 years.
New Engl. J. Med. (1992) 326:1187-1191
ADULT LUNG TRANSPLANTATION FOR CF
Kaplan-Meier Survival (Transplants: January 1994 – June 2003)
0
25
50
75
100
0 1 2 3 4 5 6 7 8 9 10Years
Surv
ival
(%)
A CFTR Potentiator in Patients with CF and the G551D Mutation
• Ivacaftor for 48 weeks in 145 CF patients with G551D
• Sustained increase in FEV1 of 10% at 48 weeks
• Decrease in sweat chloride
Improvements in risk of pulmonary exacerbation and weight
• NEJM 2011; 365: 1663-1672
Therapy for Cystic Fibrosis-
The End of the Beginning
P.B. Davis
NEJM 2011; 365: 1734-1735
Questions for the Future• Will Kalydeco be useful for other
mutations?• Will it prevent lung disease if started in the
newborn period?• Will it enable patients to do less
maintenance therapy and still achieve good outcomes?
• Will other mutation specific drugs follow?• Will it become less expensive?
CF Summary• Common genetic disease• Shorter average life expectancy• Variable clinical manifestations• Diagnosis - clinical plus laboratory• Prenatal diagnosis and newborn screen
available• Current treatment is preventive and
symptomatic• New, mutation specific, small molecule RX
CF Pulmonary Guidelines
• Chronic Medications for Maintenance of Lung Health. Am. J. Resp. Crit. Care Med. 176: 957-969, 2007.
• Airway Clearance Therapies. Respiratory Care. 54:522, 2009
• Treatment of Pulmonary Exacerbations. AJRCCM. 180: 802, 2009