Is It Cystic Fibrosis? Identifying Patients With Atypical CF
Management and Treatment of Patients with Cystic fibrosis ..."Management and Treatment of Patients...
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"Management and Treatment of Patients with Cystic fibrosis (CF)” Dr. Malena Cohen-Cymberknoh Pediatric Pulmonology and CF Center Hadassah Hebrew-University Medical Center Jerusalem, Israel Afula, March 1 st 2017
Transcript of Management and Treatment of Patients with Cystic fibrosis ..."Management and Treatment of Patients...
"Management and Treatment of Patients with
Cystic fibrosis (CF)”
Dr. Malena Cohen-Cymberknoh Pediatric Pulmonology and CF Center Hadassah Hebrew-University Medical Center
Jerusalem, Israel
Afula, March 1st 2017
CF- Introduction
• CF is the most common serious genetic disease
• Previously patients died in early infancy and childhood • For those born in 2000, the UK CF data estimate survival
greater than 50 years
• Advances in CF care are largely responsible for the improved lifespan
• New therapies directed towards underlying defect promise to open a new era of CF therapeutics
Genetics of CF- the CFTR gene
• Autosomal-recessive Inheritance
• In 1989 the CFTR gene was discovered
• The CFTR gene resides on the long arm of chromosome 7
• More than 1800 mutations in the CFTR gene associated with disease have been reported
• The most common mutation- DelF508 (75%)
Ca2+
Cl- Cl- cAMP
Na+ K+
K+ K+ 2Cl- Na+
H2O
Na+ Cl-
H2O
Na+ Cl-
CFTR ENaC
CFTR gene mutation
CFTR defect
Electrolyte transport abnormalities
Infection Inflammation
Progressive lung damage
Death
Neutrophil dominated Bacterial
Excesive/abnormal mucus production
Respiratory Presentations of CF
• Chronic cough • Recurrent/ chronic bronchitis or pneumonia • Severe wheezing/ hyperinflation • Tachypnea/ retractions • Atelectasis • Hemoptysis • Pneumothorax • Bronchiectasis • Staph/ Pseudomonas colonization in the respiratory tract • Chronic pansinusitis • Nasal polyps • Clubbing
Incidence of Major Airway Pathogens by Patient Age
Cystic Fibrosis Patient Registry 2010
Pseudomonas aeruginosa in the CF lungs
• Chronic P. aeruginosa (PA) lung infection is the cause of much of the morbidity and most of the mortality in CF patients
• ~80% of CF adults have chronic PA infection; once a chronic infection is established, it is very difficult to eradicate
• Aggressive early eradication therapy have to be initiated as soon as the pathogen is detected, which can delay the onset of chronic infection
• Risk of eradication failure increased by with delayed CF diagnosis • Successful eradication increased with each additional sputum culture taken • Delayed detection of PA infection leading to delayed treatment and growth of multi-
resistant organisms is associated with eradication failure
M. Cohen-Cymberknoh et al, Journal of Cystic fibrosis 2016
Gastrointestinal Presentations of CF
• Meconium ileus (~15%) • Prolonged neonatal jaundice • Steatorrhea • Rectal prolapse • Mucoid impacted appendix • Recurrent intussusception • Recurrent pancreatitis • Liver disease ~30%- fatty liver, focal/multilobar biliary cirrhosis • Distal Intestinal Obstruction Syndrome (DIOS)
Metabolic Presentations of CF
• Salty taste • Failure to thrive • Hypoproteinemia, edema • Vitamin A, E, D deficiency • Hemolytic anemia (Vitamin E deficiency) • Salt depletion - Metabolic alkalosis • Azoospermia/CBAVD- male infertility (98%)
• One or more characteristic clinical features of CF or • a family history of CF • positive neonatal screening Together with:
• Abnormal sweat chloride values on 2 occasions or • abnormal Nasal Potential Difference (NPD) • identification of two (CFTR) mutations
CF diagnostic consensus, Rosenstein et al. J Pediatr 1998
CF diagnosis
Sweat test • Gold standard to diagnose CF • Results: Cl > 60 mmol/l- positive Cl < 40 mmol/l- negative Cl = 40-60 mmol/l- borderline
NPD
Classic and non-classic CF
(>95%)
Early pulmonary involvement
(CBAVD) (CBAVD)
* * * *
21 y.o. male CF-PI patient
21 y.o. male CF-PS patient
Simanovsky and Cohen-Cymberknoh et al, Chest 2013
A more negative correlation between FEV1% and Age in the CF-PI group
No correlation between FEV1% and %BMI in the CF-PS group
Good correlation between TBS and Age in the CF-PI and CF-PS groups
M. Cohen-Cymberknoh, Chest 2014
Good correlation between FEV1% vs. TBS in the CF-PI and CF-PS groups
“…a comparison of disease characteristics for (PCD and) CF should distinguish between CF-PI and CF-PS as different entities”
“The 10 Golden Rules of CF Care”
Cohen-Cymberknoh et al, ERJ 2014
1.Maintain good nutrition and correct nutritional deficiencies 2.Daily chest physiotherapy 3.Enhance mucociliary clearance (inhaled hypertonic saline & Pulmozyme) 4.Avoid and early treat new acquisition of pseudomonas infection 5.Suppression of chronic pseudomonas infection (inhaled antibiotics) 6.Early and aggressive treatment of pulmonary exacerbation 7.Anti-inflammatory therapy 8.Early identification and treatment of complications 9.Centered care with frequent regular visits 10.Strict adherence to all the above therapies
Five Class CFTR Mutations
R
Class I No protein synthesis (W1282X)
R
Class II Protein processing (DelF508)
R
Cl-
Class IV Impaired Conductance (R1152H)
R
Cl-
Class V Reduced number
R Class III Regulation (G551D)
X A new type of individualized
treatment in CF: Mutation class specific therapy
Normal I II III IV V
G542X G551D R117H D1152H
3849+10kbC–>T 5T
F508del
A455E
No synthesis
Block in processing
Altered conductance
Block in regulation
Reduced synthesis
Classes of CFTR Mutations
87% 12% 5% 5% 5%
W1282X
• Premature Stop Mutations • 60% in Ashkenazi Jewish patients
Normal Translation
Full-length Protein
Ribosomes
Amino acid
Normal Stop
Codon
Protein mRNA
Normal Flow of Genetic Information Results in Full-Length Protein Production
Premature Termination
Truncated Protein
Nonsense (Premature Stop)
Codon
Normal Stop
Codon
Protein mRNA
Nonsense Mutation Halts the Flow of Genetic Information and Results in Truncated Protein
Production
YIELD
Ataluren
Full-length Protein
Normal Stop
Codon
Nonsense (Premature Stop)
Codon
Ataluren Has Been Designed to Overcome Nonsense Mutations
Protein mRNA
Mean relative change in percent-predicted FEV1 from baseline to week 48
Kerem E et al. Lancet Respir Med. 2014
Ataluren is already registered for patients with Duchenne Muscular Dystrophy carrying nonsense mutations
Normal I II III IV V
G542X G551D R117H D1152H
3849+10kbC–>T 5T
F508del
A455E
No synthesis
Block in processing
Altered conductance
Block in regulation
Reduced synthesis
Classes of CFTR Mutations
87% 12% 5% 5% 5%
W1282X
• CFTR gating mutations • CFTR that not open and close
properly
• Improves sweat chloride levels • Improves lung function • Improves weight • Improves time-to-first pulmonary exacerbation • Improves OGTT and insulin secretion
Ivacaftor (Kalydeco), a CFTR potentiator for Class 3 mutations
2012
Normal I II III IV V
G542X G551D R117H D1152H
3849+10kbC–>T 5T
F508del
A455E
No synthesis
Block in processing
Altered conductance
Block in regulation
Reduced synthesis
Classes of CFTR Mutations
87% 12% 5% 5% 5%
W1282X
F508del Results in Defective Processing, Defective Gating, and Reduced Surface Stability
• The F508del mutation affects the processing and trafficking of the resultant CFTR proteins
• The result is little to no CFTR protein delivered to the apical cell surface
• The small amount of F508del-CFTR that may reach the apical cell surface has reduced function and accelerated turnover
Wang XR, Li C. Biomolecules 2014
ER
Golgi
Nucleus
Proteasome
Increased Activity of DF508 CFTR with Lumacaftor in Combination with Ivacaftor
F508del-CFTR
Modified from Van Goor et al. PNAS 2011
F508
del-C
FTR
Chl
orid
e Tr
ansp
ort
(%
of n
orm
al C
FTR
)
No drug ivacaftor Alone (3 𝞵𝞵M)
lumacaftor + ivacaftor
(3𝞵𝞵M + 3𝞵𝞵M)
lumacaftor Alone (3 𝞵𝞵M)
30
20
10
40
0
P=0.0189
P=0.0033
+ CFTR corrector (Lumacaftor)
P=0.0119
P=0.0288
+ CFTR potentiator (Ivacaftor)
+ CFTR potentiator (Ivacaftor)
Our Orkambi experience
0
10
20
30
40
50
60
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
ppFEV1 before and after Orkambi
One patient homozygous for Phe508del 40 y/o, married + 3 Severe lung disease, CF-related diabetes
Orkambi months
Sheba Carmel Schneider Soroka Rambam Hadassah
175
33
77
135
96
171
Number of patients with CF in Israel 687n=
Males / Females 56% / 44%
Pulmonary function (FEV1 median) in Israel
58606264666870727476
70.7%
Patients≥18y= 58%
Percentage of adult CF patients in Israel
43
52 53.4
58
30
35
40
45
50
55
60
1 2 3 4
58%
2013
EU 51.8%
2011 2009 2007
CF Survival is Improving
Orkambi
Restore CFTR function CFF Drug Pipeline
Dorothy Andersen, 1938
