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Cystic Fibrosis
1938CYSTIC FIBROSIS OF THE PANCREAS
AND ITS RELATION TO CELIAC DISEASE.
D ANDERSEN.American Journal Diseases Children.
Cystic Fibrosis : The beginningCystic Fibrosis : The beginning
20
25
May 1938: 49 cases
0
5
10
15Nos of cases
0.5 1 1.5 2 2.5 3 3.5 4 4.5 5
Age at death
Cystic Fibrosis
Commonest lethal inherited condition in WWCommonest lethal inherited condition in WWLife limiting and incurable.Life limiting and incurable.
600 ti t i Vi t i ith CF600 ti t i Vi t i ith CF600 patients in Victoria with CF.600 patients in Victoria with CF.One in every 2,500 live birthsOne in every 2,500 live births
About 15About 15--25 new born pts per year25 new born pts per year
Cystic Fibrosis
Median age survival late 30’s Median age survival late 30’s 95% survive till 20 years 95% survive till 20 years
80% till 30 years80% till 30 years80% till 30 years80% till 30 years
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Cystic Fibrosis
New Born screening: HitsNew Born screening: HitsAll states of AustraliaDay 3Day 32 part test: IRT and CF genePositive results by 4-6 weeks
Cystic Fibrosis
New Born screeningNew Born screening2 part test: IRT top 1%
CF genotypeCF genotype
Cystic Fibrosis
CF gene:CF gene:Over 1500 different mutationsΔ508 commonest present in 90% pts in AustraliaΔ508 commonest - present in 90% pts in AustraliaCurrent Vic program screens for 13 commonestMutations screened for differ between states
CYSTIC FIBROSISCYSTIC FIBROSIS
GENOTYPES 5 ClassesClass 1: Premature termination of mRNA translation
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CYSTIC FIBROSISCYSTIC FIBROSIS
GENOTYPES Class 1: Premature termination of mRNA translation
due to base substitution causing stop codonsdue to base substitution causing stop codons
CYSTIC FIBROSISCYSTIC FIBROSIS
GENOTYPES Class 1: Premature termination of mRNA translation
due to base substitution causing stop codonsdue to base substitution causing stop codonsor mutations that shift the reading frame Producing defective proteins
CYSTIC FIBROSISCYSTIC FIBROSIS
GENOTYPES Class 1: Premature termination of mRNA translation
due to base substitution causing stop codonsdue to base substitution causing stop codonsor mutations that shift the reading frame Producing defective proteins
G542X and W1282X
CYSTIC FIBROSISCYSTIC FIBROSIS
GENOTYPES Class 2: Defects in protein processing
CFTR is degraded in ER and does not reachCFTR is degraded in ER and does not reach apical membrane
508 and N1303K
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CYSTIC FIBROSISCYSTIC FIBROSIS
GENOTYPES Class 3: Regulatory mutations
CFTR reaches apical membrane but failsCFTR reaches apical membrane but failsrespond to activation signals
G551D
CYSTIC FIBROSISCYSTIC FIBROSIS
GENOTYPES Class 4: Defective protein conduction
Reaches apical membrane but has alteredReaches apical membrane but has altered channel properties
R117H and R347P
CYSTIC FIBROSISCYSTIC FIBROSIS
GENOTYPES Class 5: Reduced levels of RNA for CFTR
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Cystic Fibrosis
New Born screening: MissesNew Born screening: MissesChronic Cough
Cystic Fibrosis
New Born screening: MissesNew Born screening: MissesChronic CoughFailure to thriveFailure to thrive
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Cystic Fibrosis
New Born screening: MissesNew Born screening: MissesChronic CoughFailure to thriveFailure to thriveChronic Diarrhoea
Underlying defect in CFUnderlying defect in CF
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Mechanisms of lung damage in CF
Viscous secretions
Viscous secretions
CFTR dysfunction
CFTR dysfunction
InfectionInfection InflammationInflammation
Lung damage
Abnormal lung function
Lung damage
Abnormal lung function
DeathDeath
secretionssecretions
CF update: Early lung disease
Aim to minimise/ delay onset disease thru new born screening
Early intervention in CF patientsprevents severe malnutrition
• Wisconsin CF Neonatal Screening Study
• Randomised controlled trial with 650,000 newborns. Split into two groups:Split into two groups:– an early-diagnosis screened cohort– a standard diagnosis control group
• Newborns screened for CF by– immunoreactive trypsinogen (IRT) test (1985-91)– IRT test + DNA-based detection of ΔF508 (1991-94)
Effect of screening on weight
-0.6-0.4-0.2
00 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
t SD
S
-1.8-1.6-1.4-1.2
-1-0.8
ScreenedUnscreened
Wei
ght
p<0.05
CF update: Early lung disease
Aim to minimise thru NBSRegular assessments: BAL
CT ScansCT ScansPFT’s
CF update: Early lung disease
Regular assessments: BAL30% infants will have Pseudomonas by age 3
Linnane B
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CF update: Early lung disease
Regular assessments: BAL30% infants will have Pseudomonas by age 3 despite aggressive cross infection policiesgg p
CF update: Early lung disease
Regular assessments: BAL30% infants will have Pseudomonas by age 3 despite aggressive cross infection policiesgg pAggressive eradication programs – 85% successful
CF update
Reculture:Sputum or BAL
+ve sample culture for
P. aeruginosa
Nebulised tobramycinNebulised tobramycin
Cipro Cipro
3 months? IV’s
POSITIVE NEGATIVE
2 weeks of IV anti-pseudomonal
antibiotics and then repeat
No further treatment or back to prophylactic
antibiotics
If following second attempt of eradication sputum or BAL is still positive is likely chronic Pa infection
CF update: Early lung disease
Regular assessments: BAL30% infants will have Pseudomonas by age 3 despite aggressive cross infection policiesgg pAggressive eradication programs – 85% successfulPseudomonas EVER is a bad prognostic factor
CF update: Early lung disease
Regular assessments: CT scans90% infants will show signs of bronchiectasis
on CT at age 5 yearson CT at age 5 years
Wainwright C
CF update: Early lung disease
Regular assessments: PFT’sChanges occur very early and are progressive
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Linnane B
CF update: Early lung disease
Future management? Trials anti inflammatory Medication
CF update: Early lung disease
Future management? Trials anti inflammatory Medication -
AZTAZT
CF update Antibiotic therapy in CF
TargetedNon Pseudomonal: Staph/ H Inf
Incidence airway pathogens by age
60
80
100S. aureusH. influenzae
ture
s (%
)
0
20
40
0-1 2-5 6-10 11-15 16-20 21-25 26-30 31-35 >35
Age group (years)
Tota
l cul
t
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CYSTIC FIBROSISCYSTIC FIBROSIS
B. CEPACIAGenomovars (1-9)Aggressive lung disease (cenocepacia type 3)Aggressive lung disease (cenocepacia type 3)Non 3 mild diseaseBactrimSome clearance
CYSTIC FIBROSISCYSTIC FIBROSIS
ASPERGILLUSABPAAirway colonisationAirway colonisationAspergillomaInfection in pre existing cyst
Incidence airway pathogens by age
60
80
100 P. aeruginosaS. aureusH. influenzae
ture
s (%
)
0
20
40
0-1 2-5 6-10 11-15 16-20 21-25 26-30 31-35 >35
Age group (years)
Tota
l cul
t
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