genetics of cf wehe dem kind, das beim kuss auf die stirn … · 2 cftr abnormalities in the cftr...
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CYSTIC FIBROSISCYSTIC FIBROSIS
Lynne M. Quittell, M.D.Lynne M. Quittell, M.D.Director, CF CenterDirector, CF CenterColumbia UniversityColumbia University
What is Cystic Fibrosis?What is Cystic Fibrosis?
Chronic, progressive and life limiting Chronic, progressive and life limiting autosomal recessive genetic disease autosomal recessive genetic disease characterized by chronic respiratory characterized by chronic respiratory disease, pancreatic insufficiency, disease, pancreatic insufficiency, elevation of sweat electrolytes and elevation of sweat electrolytes and male infertilitymale infertility
Genetics of CFGenetics of CFMost common lethal genetic disease in Most common lethal genetic disease in CausasiansCausasians
30,000 affected individuals in US30,000 affected individuals in US27,000 in Europe27,000 in Europe
CFTR CFTR -- cAMPcAMP regulated chloride channel regulated chloride channel located in apical membrane of glandular located in apical membrane of glandular epithelium epithelium –– Long arm of chromosome #7Long arm of chromosome #7
D508 most common mutationD508 most common mutation1000 identified mutations1000 identified mutations
–– Encodes for a protein of 1480 amino acidsEncodes for a protein of 1480 amino acids–– Defective ion transportDefective ion transport
““Wehe dem Kind, das beim Wehe dem Kind, das beim Kuss auf die Stirn salzig Kuss auf die Stirn salzig
schmekt, er ist verhext und schmekt, er ist verhext und muss bald sterbenmuss bald sterben””
““Woe is the child who tastes salty Woe is the child who tastes salty from a kiss on the brow, for he is from a kiss on the brow, for he is cursed , and soon must diecursed , and soon must die””
PresentationPresentation(CF PANCREAS)(CF PANCREAS)
CC Chronic respiratory diseaseChronic respiratory diseaseFF Failure to thriveFailure to thriveP P PolypsPolypsA A Alkalosis, metabolicAlkalosis, metabolicN N Neonatal intestinal obstructionNeonatal intestinal obstructionCC Clubbing of fingersClubbing of fingersRR Rectal prolapseRectal prolapseE E Electrolyte Electrolyte in sweatin sweatAA Aspermia / absent vas deferensAspermia / absent vas deferensSS Sputum Sputum –– S.aureus/P.aeruginosaS.aureus/P.aeruginosa
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CFTRCFTR
Abnormalities in the CFTR protein change Abnormalities in the CFTR protein change the constituents of mucous and result in the constituents of mucous and result in abnormal abnormal reabsorptionreabsorption of water, creating of water, creating thickened mucus and inadequate thickened mucus and inadequate mucociliarymucociliary function.function.The CF airway has many changes leading The CF airway has many changes leading to mucous plugging, chronic infection, and to mucous plugging, chronic infection, and inflammation.inflammation.
CFTRCFTR HypothesisHypothesis
L ys o zy m eL ac tofer in , S L P I
P h os ph o lipa se A 2S e creto ry IgA
S P -A , S P -D , N Oh B D-1, h B D-2, L L-3
Cl-Na+
PhagocyticCells Cl-
Na+CFTR
AcquiredImmunity
MucociliaryClearance
MucusPlug
NFκβIL-8
The Cystic Fibrosis AirwayThe Cystic Fibrosis Airway
Used with permission - R. Gibson, 2004.
Neutrophils
Bacteria
Muc
us
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The sweat test ( Chloride)The sweat test ( Chloride)
NormalNormalUnder 40 mEq/LUnder 40 mEq/L
BorderlineBorderline4040--60 mEq/L60 mEq/L
PositivePositiveOver 60 mEq/LOver 60 mEq/L
CF: Pulmonary DiseaseCF: Pulmonary Disease Pathogenesis of Cystic Fibrosis Pathogenesis of Cystic Fibrosis Lung DiseaseLung Disease
CF Gene
Mucous PluggingInfection
Inflammation
MorbidityMortality
AbnormalCFTR
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Airway Mucous Plugging, Airway Mucous Plugging, Infection, and Inflammation in Infection, and Inflammation in
Cystic FibrosisCystic Fibrosis
Used with permission – J. Wagener, 2004.
0
20
40
60
80
100
Age (y)
Total Cultures
(%)
Major Airway Pathogens by Major Airway Pathogens by Patient Age, 1999Patient Age, 1999
P aeruginosa
S aureus
H influenzae
90
70
50
30
10B cepaciaS maltophilia
0–1 2–5 6–10 11–17 18–24 25–34 35–44 ≥ 45
Patient Registry 1999 Annual Data Report. Bethesda, Md: Cystic Fibrosis Foundation; 2000.
Evidence of increased Evidence of increased inflammation in BALF of infants inflammation in BALF of infants
with CFwith CF
Adapted from Muhlebach et al. Am J Respir Crit Care Med 1999; 160: 186-191.
(n = 23) (n = 27) (n = 23) (n = 28)Uninfected Infected Uninfected Infected
0
20
40
60
80
% Neutrophils
0
5
10
15
20
25
IL-8 (ng/ml)
Controls
CF
DNA in DNA in BronchoalveolarBronchoalveolar Lavage Lavage Fluid from Fluid from Cystic Fibrosis Cystic Fibrosis
PatientsPatients
0
1
2
3
4
5
6
7
8
9
Control CF-Infant CF-Older
DN
A (µ
g/m
l)
Kirchner et al. Am J Respir Crit Care Med 1996; 154: 1426-1429.
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CF Lung: EndCF Lung: End--Stage Stage BronchiectasisBronchiectasis
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CF Lung FunctionCF Lung Function
Lung function in CFLung function in CF
AA--a gradienta gradientcompliancecomplianceflow rates at low lung volumesflow rates at low lung volumesslope of phase III nitrogen washoutslope of phase III nitrogen washoutphysiologic dead spacephysiologic dead spaceexercise toleranceexercise tolerance
Signs and Symptoms of Signs and Symptoms of Pulmonary ExacerbationPulmonary Exacerbation
Increased coughIncreased coughIncreased sputumIncreased sputumWeight lossWeight lossSchool/work School/work absenteeismabsenteeismIncreased dyspneaIncreased dyspnea
New chest findingsNew chest findings–– rales, wheezesrales, wheezes
Decreased exercise Decreased exercise tolerancetoleranceDecreased FEV1Decreased FEV1–– down 10%down 10%
New radiographic New radiographic findingsfindings
CF mild diseaseCF mild diseaseBronchiectasis
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HighHigh--Resolution Inspiratory and Resolution Inspiratory and Expiratory CT Scan in 12 year oldExpiratory CT Scan in 12 year old
Used with permission - C. Milla, 2004.
CF PneumothoraxCF Pneumothorax
BLEBSBLEBS
CF: Pulmonary ComplicationsCF: Pulmonary Complications
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Exacerbations Contribute to the Exacerbations Contribute to the Deterioration of Lung FunctionDeterioration of Lung Function
0
20
40
60
80
100
Age (y)
FEV1(% predicted)
Exacerbations
After treatment
• Acute exacerbations with some reversibility• Chronic decline
Used with permission from P. Flume.
CF: Respiratory managementCF: Respiratory management
Regular visits to CF CenterRegular visits to CF CenterAirway clearanceAirway clearanceMucus thinners (Mucus thinners (DNaseDNase, , hypertonic saline)hypertonic saline)Antibiotics( POAntibiotics( PO--IVIV--Aerosol)Aerosol)Anti inflammatory drugsAnti inflammatory drugs
Airway ClearanceAirway Clearance
CPTCPTVestVestFlutterFlutterACBACB
RefluxRefluxRisk factor for Risk factor for PaPaAdherenceAdherence
ISSUES
CF FlutterCF Flutter
AntiAnti--inflammatory Rxinflammatory Rx
SteroidsSteroids–– inhaled v oralinhaled v oral
IbuprofenIbuprofenMacrolidesMacrolides
SafetySafetyAdherenceAdherence? Delay in ? Delay in progression of the progression of the diseasedisease
ISSUES
Diffuse PanDiffuse Pan--bronchiolitis (DPB)bronchiolitis (DPB)
DPB clinically resembles CFDPB clinically resembles CF–– More common in Japan than in Western countries More common in Japan than in Western countries –– Age of onset between 30 and 60 years of ageAge of onset between 30 and 60 years of age
Chronic lower respiratory tract infectionChronic lower respiratory tract infection–– Neutrophils predominant inflammatory cell Neutrophils predominant inflammatory cell –– H. influenzaeH. influenzae andand S. pneumoniaS. pneumonia early in disease early in disease –– P. aeruginosa P. aeruginosa major pathogen latermajor pathogen later
70% of patients have mucoid strains70% of patients have mucoid strains–– Progress to bronchiectasis and respiratory failureProgress to bronchiectasis and respiratory failure
Pancreatic insufficiency Pancreatic insufficiency notnot a clinical featurea clinical feature
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Relative Change in FEV1 % Predicted
0 28 84 168 196
-4
-2
0
2
4
5
Study Day
Azithromycin
Placebo
Day 168 Treatment Effect:6.21% (p=0.001)
Day 168 Δ: 4.44%
Day 168 Δ : -1.77%
DNaseDNase
Recombinant Recombinant DNaseDNaseHydrolyzes DNAHydrolyzes DNAAerosolizedAerosolized
Treating Airway infectionsTreating Airway infections
Prophylactic treatmentProphylactic treatment–– prevent colonizationprevent colonizationExacerbationsExacerbations–– improves lung functionimproves lung function–– reduces inflammationreduces inflammation–– decreases bacterial densitydecreases bacterial densityFirst isolatesFirst isolates–– may delay colonizationmay delay colonization
AntibioticsAntibiotics
OralOralIVIVAerosolizedAerosolizedSpecial Considerations:Special Considerations:–– Volume of distributionVolume of distribution–– SensitivitiesSensitivities–– Drug InteractionsDrug Interactions–– Side effectsSide effects
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CF PFTCF PFT’’ss CF: Gastrointestinal DiseaseCF: Gastrointestinal Disease
Pancreatic insufficiency/malabsorptionPancreatic insufficiency/malabsorptionLipoLipo--soluble vitamin deficiencysoluble vitamin deficiencyFailure to thriveFailure to thriveNeonatal intestinal obstruction (15%)Neonatal intestinal obstruction (15%)Recurrent distal intestinal obstructionRecurrent distal intestinal obstructionBiliary stasis Biliary stasis
CF: PancreasCF: Pancreas--malabsorptionmalabsorption
Nutrition and CFNutrition and CF
75
80
85
90
95
100
105
FEV1% at age 6
<5 25-50 >50WFA percentile at age 3
5-9 10-24
Konstan et. Al. Pediatr Pulmonol 2000
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SUMMARYSUMMARY
Need to understand the pathophysiology Need to understand the pathophysiology of CF lung disease in young patientsof CF lung disease in young patientsNeed to understand the risk/benefit ratio of Need to understand the risk/benefit ratio of new treatmentsnew treatmentsAdherenceAdherenceWindow of opportunityWindow of opportunityChanging landscapeChanging landscape