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