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Cystic Fibrosis Cystic Fibrosis Esmeralda E. Morales, MD Esmeralda E. Morales, MD August 28, 2006 August 28, 2006

CYSTIC FIBROSIS KNOW IT NOW!

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Cystic fibrosis (also known as CF or mucoviscidosis) is a recessive multi-system genetic disease characterized by abnormal transport of chloride and sodium across epithelium, leading to thick, viscous secretions in the lungs, pancreas, liver, intestine.[Yankas JR, et al. (2004). "Cystic fibrosis adult care consensus conference report". Chest 125: 1-39.]

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Page 1: CYSTIC FIBROSIS KNOW IT NOW!

Cystic FibrosisCystic Fibrosis

Esmeralda E. Morales, MDEsmeralda E. Morales, MD

August 28, 2006August 28, 2006

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ObjectivesObjectives

Know the clinical features of cystic Know the clinical features of cystic fibrosis.fibrosis.

Know how CF is inherited.Know how CF is inherited. Be familiar with criteria to diagnose Be familiar with criteria to diagnose

CF.CF. Become aware of the myriad of Become aware of the myriad of

treatments used in CF.treatments used in CF.

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What is cystic fibrosis What is cystic fibrosis (CF)?(CF)?

A multisystem diseaseA multisystem disease Autosomal recessive inheritanceAutosomal recessive inheritance Cause: mutations in the cystic Cause: mutations in the cystic

fibrosis transmembrane conductance fibrosis transmembrane conductance regulator (CFTR)regulator (CFTR) chromosome 7 chromosome 7 codes for a c-AMP regulated chloride codes for a c-AMP regulated chloride

channelchannel

Rosenstein, BJ and Zeitlin, PL. Cystic fibrosis. The Lancet. 351: 277-82.

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Diagnosis of cystic Diagnosis of cystic fibrosisfibrosis

One or more clinical features of CFOne or more clinical features of CF PLUSPLUS Two CF mutationsTwo CF mutations OROR Two positive quantative pilocarpine Two positive quantative pilocarpine

iontophoresis sweat chloride valuesiontophoresis sweat chloride values OROR An abnormal nasal transepithelial An abnormal nasal transepithelial

potential difference value potential difference value

Cystic Fibrosis Foundation. Clinical Practice Guidelines for Cystic fibrosis.1997.

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Clinical features of Cystic Clinical features of Cystic FibrosisFibrosis

Chronic Sino-Pulmonary DiseaseChronic Sino-Pulmonary Disease Nutritional deficiency/GI Nutritional deficiency/GI

abnormalityabnormality Obstructive AzoospermiaObstructive Azoospermia Electrolyte abnormality Electrolyte abnormality CF in a first degree relativeCF in a first degree relative

Cystic Fibrosis Foundation. Clinical Practice Guidelines for Cystic fibrosis.1997.

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Welsh, MJ and Smith, AE. Cystic Fibrosis. Scientific American. 273 (6): 52, 1995.

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Burden of CFBurden of CF Most common “life-shortening” Most common “life-shortening”

recessive genetic disease in recessive genetic disease in Caucasians Caucasians 1:3,500 newborns in the US1:3,500 newborns in the US 1 in 10,500 Native Americans1 in 10,500 Native Americans 1 in 11,500 Hispanics1 in 11,500 Hispanics 1 in 14,000 to 17,000 African 1 in 14,000 to 17,000 African

AmericansAmericans 1 in 25,500 Asians 1 in 25,500 Asians

http://www.cff.orghttp://www.cff.org

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Burden of CF Burden of CF (continued)(continued)

About 30,000 people affected About 30,000 people affected in United States in United States

>10,000,000 people carriers of >10,000,000 people carriers of mutant CFTRmutant CFTR

80% cases diagnosed by age 380% cases diagnosed by age 3 Almost 10% diagnosed ≥18 Almost 10% diagnosed ≥18

yearsyearshttp://www.cff.orghttp://www.cff.org

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CF SurvivalCF Survival Overall trend is improved survivalOverall trend is improved survival Female survival worse than male between 2-Female survival worse than male between 2-

20 years of age20 years of age11

35% of patients are older than 18 years of 35% of patients are older than 18 years of ageage22

Median survival 36.8 yearsMedian survival 36.8 years3 3 compared to compared to 1930s when life expectancy was about 6 1930s when life expectancy was about 6 monthsmonths22

1.Goss, CH and Rosenfeld, M. Update on cystic fibrosis epidemiology. Current Opinion in

Pulmonary Medicine. 10:510-514; 2004.2. Davis, P. Cystic Fibrosis Since 1938. AJRCCM Articles in Press.

Doi: 10.1164/rccm.200505-840OE; 2005. 3.www.cff.org/news/general_news

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Autosomal recessive Autosomal recessive inheritance in CFinheritance in CF

Let Let CC= normal CFTR= normal CFTR

Let Let cc= mutant CFTR= mutant CFTR

If mom and dad are If mom and dad are both carriers then: both carriers then:

With mom and dad With mom and dad carriers, then:carriers, then: 50% chance of 50% chance of

having child who is having child who is a carriera carrier

25% chance of 25% chance of child being affectedchild being affected

25% of child with 25% of child with no mutant copies of no mutant copies of CFTRCFTR

CC

Cc

Cc

cc

C c

C

c

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Cystic fibrosis Cystic fibrosis transmembrane transmembrane

conductance regulator conductance regulator (CFTR) gene(CFTR) gene The CFTR gene is The CFTR gene is

located on the long arm located on the long arm of chromosome 7.of chromosome 7.

There are 1522 There are 1522 mutations in CFTR mutations in CFTR listed on the CFTR listed on the CFTR mutation database mutation database (http://www.genet.sickk(http://www.genet.sickkids.on.ca/cftr/)ids.on.ca/cftr/)

The most common The most common mutation is mutation is ΔΔ F508--- F508---70% CF alleles in 70% CF alleles in caucasians.caucasians.11

http://www.ornl.gov/sci/techresources/Human_Genome/posters/chromosome/cftr.shtml

1. Gibson, RL, Burns, JL, and Ramsey, BW. Pathophysiology and Management of

PulmonaryInfections in Cystic Fibrosis. AJRCCM 168

(918-951);2003.

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Cell membrane diagramCell membrane diagram

From: http://library.thinkquest.org/C004535/cell_membranes.html

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CFTRCFTR

Gibson, RL, Burns, JL, and Ramsey, BW. Pathophysiology and Management of Pulmonary Infections in Cystic Fibrosis. AJRCCM 168 (918-951); 2003.

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Types of mutations in Types of mutations in CFTRCFTR

Class IClass I Defective protein Defective protein

productionproduction Class IIClass II

Defects in processingDefects in processing ΔΔF508F508

Class IIIClass III CFTR reaches cell surface CFTR reaches cell surface

but regulation is defective but regulation is defective (channel not activated)(channel not activated)

Class IVClass IV CFTR in membrane with CFTR in membrane with

defective conductiondefective conduction Class VClass V

Decreased synthesis of Decreased synthesis of CFTRCFTRhttp://www.cysticfibrosismedicine.com/

htmldocs/CFText/genetics.htm

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CFTR and Airway Surface CFTR and Airway Surface LiquidLiquid

Donaldson,SH and Boucher,RC. Update on the pathogenesis of cystic fibrosis lung disease.Current Opinion in Pulmonary Medicine. 9: 486-491; 2003.

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Airway surface liquid low Airway surface liquid low volume hypothesisvolume hypothesis

Mucus---helps clear airway of bacteriaMucus---helps clear airway of bacteria Clearance of mucus depends on Clearance of mucus depends on

Ciliary functionCiliary function Mucin secretion Mucin secretion Volume of airway surface liquid (ASL) Volume of airway surface liquid (ASL)

Forms periciliary liquid layerForms periciliary liquid layer Dilutes mucus---facilates entrapment of Dilutes mucus---facilates entrapment of

bacteria and clearancebacteria and clearance Optimal volume of ASL regulated by Na+ Optimal volume of ASL regulated by Na+

absorption and Cl- secretionabsorption and Cl- secretion

Donaldson,SH and Boucher,RC. Update on the pathogenesis of cystic fibrosis lung disease.Current Opinion in Pulmonary Medicine. 9: 486-491; 2003.

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Airway surface liquid low Airway surface liquid low volume hypothesis and volume hypothesis and

CFTRCFTR Normal CFTR inhibits a sodium Normal CFTR inhibits a sodium channel (ENaC)channel (ENaC) Mutant CFTR----ENaC not inhibitedMutant CFTR----ENaC not inhibited

Sodium absorption is increasedSodium absorption is increased Water follows sodiumWater follows sodium ASL volume decreasesASL volume decreases

Normal CFTR will cause Cl- ions to Normal CFTR will cause Cl- ions to be secreted if the ASL fluid is lowbe secreted if the ASL fluid is low Mutant CFTR Cl- ions not secreted Mutant CFTR Cl- ions not secreted

Donaldson,SH and Boucher,RC. Update on the pathogenesis of cystic fibrosis lung disease.Current Opinion in Pulmonary Medicine. 9: 486-491; 2003.

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Airway surface liquid low Airway surface liquid low volume hypothesis and volume hypothesis and

consequencesconsequences Cilia do not beat well when PCL Cilia do not beat well when PCL

volume is depletedvolume is depleted Mucins are not diluted and cannot Mucins are not diluted and cannot

be easily swept up the airway be easily swept up the airway Mucus becomes concentratedMucus becomes concentrated

Results in increased adhesion to airway Results in increased adhesion to airway surfacesurface

Promotes chronic infectionPromotes chronic infection

Donaldson,SH and Boucher,RC. Update on the pathogenesis of cystic fibrosis lung disease.Current Opinion in Pulmonary Medicine. 9: 486-491; 2003.

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CF Clinical Signs

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Chronic Sino-Pulmonary Chronic Sino-Pulmonary DiseaseDisease

Chronic infection with CF pathogens Chronic infection with CF pathogens Endobronchial diseaseEndobronchial disease

Cough/sputum productionCough/sputum production Air obstruction---wheezing; evidence of Air obstruction---wheezing; evidence of

obstruction on PFTsobstruction on PFTs Chest x-ray anomaliesChest x-ray anomalies Digital ClubbingDigital Clubbing

Sinus diseaseSinus disease Nasal PolypsNasal Polyps CT or x-ray findings of sinus diseaseCT or x-ray findings of sinus disease

Cystic Fibrosis Foundation. Clinical Practice Guidelines for Cystic fibrosis.1997.

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InfectionInfection

Gibson, RL, Burns, JL, and Ramsey, BW. Pathophysiology and Management of Pulmonary Infections in Cystic Fibrosis. AJRCCM 168 (918-951); 2003.

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CF Infections---CF Infections---Pseudomonas aeruginosaPseudomonas aeruginosa

80% CF patients eventually infected with 80% CF patients eventually infected with pseudomonas pseudomonas

Association between acquiring pseudomonas Association between acquiring pseudomonas and clinical status deteriorationand clinical status deterioration

Form biofilmsForm biofilms Relatively large genomeRelatively large genome

Pseudomonae collected from sputa of CF patients Pseudomonae collected from sputa of CF patients have been noted to have larger genomes than lab have been noted to have larger genomes than lab strainsstrains Gibson, RL, Burns, JL, and Ramsey,

BW. AJRCCM 168 (918-951); 2003.

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Pseudomonas genomePseudomonas genome

http://www.pseudomonas.com/

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Burkholderia cepaciaBurkholderia cepacia complexcomplex

B. cepaciaB. cepacia syndrome: syndrome: fevers, rapidly fevers, rapidly progressive necrotizing progressive necrotizing pneumonia, deathpneumonia, death

Chronic cepacia Chronic cepacia infection—decreased infection—decreased lung function and lung function and increased mortalityincreased mortality

Several closely related Several closely related species termed species termed genomovarsgenomovars11

III has been associated III has been associated with more severe diseasewith more severe disease

Holmes, A, Govan, J, andGoldstein, R. Agricultural Use of Burkholderia (Pseudomonas) cepacia: A Threat to Human Health?Emerging Infectious Diseases. 4(2):221-227; 1998

1. Gibson, RL, Burns, JL, and Ramsey, BW. AJRCCM 168 (918-951); 2003.

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Endobronchial diseaseEndobronchial disease

HyperinflationHyperinflation Peribronchial Peribronchial

cuffingcuffing BronchiectasisBronchiectasis Diffuse fibrosis Diffuse fibrosis AtelectasisAtelectasis

From: http://www.meddean.luc.edu/lumen/meded/elective/pulmonary/cf/cf_f.htm

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Nasal PolypsNasal Polyps Benign lesions in nasal Benign lesions in nasal

airwayairway If large enough, can be If large enough, can be

associated with associated with significant nasal significant nasal obstruction, drainage, obstruction, drainage, headaches, snoringheadaches, snoring

Likely associated with Likely associated with chronic inflammationchronic inflammation

May need surgical May need surgical interventionintervention

High recurrence rateHigh recurrence rate

From: http://www.emedicine.com/ped/topic1550.htm

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Digital ClubbingDigital Clubbing Bulbous swelling at Bulbous swelling at

end of fingersend of fingers Normal angle between Normal angle between

nail and nail bed nail and nail bed lost---Schamroth signlost---Schamroth sign

Can be associated Can be associated with pulmonary with pulmonary disease, cardiac disease, cardiac disease, ulcerative disease, ulcerative colitis, and colitis, and malignanciesmalignancies

From: Fawcett et al., 2004

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Nutritional deficiencyNutritional deficiency Pancreatic insufficiencyPancreatic insufficiency

Autopsy of malnourished infants--1938--- “cystic Autopsy of malnourished infants--1938--- “cystic fibrosis of the pancreas”---mucus plugging of fibrosis of the pancreas”---mucus plugging of glandular ductsglandular ducts11

Chloride impermeability affects HCO3- secretion and Chloride impermeability affects HCO3- secretion and fluid secretion in pancreatic ductsfluid secretion in pancreatic ducts22

Pancreatic enzymes stay in ducts and are activated Pancreatic enzymes stay in ducts and are activated intraductallyintraductally

Autolysis of pancreasAutolysis of pancreas Inflammation, calcification, plugging of ducts, fibrosis Inflammation, calcification, plugging of ducts, fibrosis

MalabsorptionMalabsorption Failure to thriveFailure to thrive Fat soluble vitamin deficiencyFat soluble vitamin deficiency

1. Davis, P. Cystic Fibrosis Since 1938. AJRCCM Articles in Press. Doi: 10.1164/rccm.200505-840OE; 2005.2. Quinton, P. Physiologic Basis of Cystic Fibrosis. Physiol Rev 79:3-22,

1999.

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GI diseaseGI disease Intestinal abnormalityIntestinal abnormality

Meconium ileusMeconium ileus Distal intestinal obstruction syndrome (DIOS)Distal intestinal obstruction syndrome (DIOS) Rectal prolapseRectal prolapse

Hepatobiliary diseaseHepatobiliary disease Focal biliary cirrhosisFocal biliary cirrhosis Multilobular cirrhosisMultilobular cirrhosis

Pancreatic endocrine dysfunctionPancreatic endocrine dysfunction Cystic fibrosis related diabetesCystic fibrosis related diabetes

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Cystic fibrosis related liver Cystic fibrosis related liver diseasedisease

Focal inspissation of bileFocal inspissation of bile Obstructs biliary ductulesObstructs biliary ductules

Second leading cause of death in CFSecond leading cause of death in CF11

Prevalence 9-37%Prevalence 9-37%11

Spectrum of disease Spectrum of disease increased liver enzymes increased liver enzymes biliary cirrhosis biliary cirrhosis portal hypertensionportal hypertension

1. Efrati, O et al., Liver Cirrhosis and portal hypertension in CF. European Journal of Gastroenterology and Hepatology. 15(10): 1073-1078; 2003.

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Cystic fibrosis related Cystic fibrosis related diabetes mellitusdiabetes mellitus

ScreeningScreening Oral glucose tolerance test (OGTT)Oral glucose tolerance test (OGTT)

Every two years in patients 10-16 yearsEvery two years in patients 10-16 years Any patient with random plasma glucose >180Any patient with random plasma glucose >180

Fasting>=140 mg/dlFasting>=140 mg/dl initiate insulin treatmentinitiate insulin treatment

Fasting<140 and OGTT at 2 hrs>200 mg/dlFasting<140 and OGTT at 2 hrs>200 mg/dl Home glucose monitoring; consider insulinHome glucose monitoring; consider insulin

Fasting <140 and 2 hour 140-200Fasting <140 and 2 hour 140-200 Impaired glucose toleranceImpaired glucose tolerance

OGTT annuallyOGTT annually Fasting and 2 hour <140Fasting and 2 hour <140

Normal glucose toleranceNormal glucose tolerance

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InfertilityInfertility

MenMen Abnormal embryologic development of Abnormal embryologic development of

the epididymal duct and vas deferens---the epididymal duct and vas deferens---may be incomplete of absentmay be incomplete of absent11

Congential bilateral absence of the vas Congential bilateral absence of the vas deferens—97-98% of men with CF deferens—97-98% of men with CF 11

1. Lewis-Jones et al, Cystic fibrosis in infertility: screening before assisted reproduction: Opinion. Human Reproduction 15(11): 2415-2417.

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InfertilityInfertility WomenWomen

Lower fertility rate than non-CF womenLower fertility rate than non-CF women Viscid mucoid cervical secretions of low Viscid mucoid cervical secretions of low

volume in women with CF volume in women with CF 11

Pregnancy and CF: Pregnancy and CF: Goss et al, 2003---no significant Goss et al, 2003---no significant

difference in survival in women who difference in survival in women who became pregnant with CF compared to became pregnant with CF compared to women who did not become pregnant women who did not become pregnant (after adjusting for disease severity)(after adjusting for disease severity)22

1.Quinton, P. Physiologic Basis of Cystic Fibrosis. Physiol Rev 79:3-22, 19992.Goss, CH, Rubenfeld, GD, Otto, K and Aitken, ML. The effect of pregnancy on survival in women with cystic fibrosis. Chest 124(4):1460-68; 2003.

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Electrolyte Electrolyte abnormality---historyabnormality---history

Dr. Paul di Sant’ Agnese Dr. Paul di Sant’ Agnese 1949 NYC heat wave----noted CF infants 1949 NYC heat wave----noted CF infants

to have a higher rate of heat prostration to have a higher rate of heat prostration than non-CFthan non-CF Showed that sodium and chloride Showed that sodium and chloride

concentration in CF patients’ sweat was 5 concentration in CF patients’ sweat was 5 times higher than in non-CFtimes higher than in non-CF11

Became basis for sweat chloride testBecame basis for sweat chloride test

1. Davis, P. Cystic Fibrosis Since 1938. American Journal of Respiratory and Critical Care Medicine Vol 173. pp. 475-482, (2006)

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Electrolyte abnormalityElectrolyte abnormality

Clinically---hypochloremic Clinically---hypochloremic metabolic alkalosismetabolic alkalosis CFTR on luminal side of sweat ductCFTR on luminal side of sweat duct

Chloride goes in from lumen via CFTR Chloride goes in from lumen via CFTR and out to blood by other transportersand out to blood by other transporters

Sodium goes in via ENaCSodium goes in via ENaC Defective CFTR---Na and Cl- movement Defective CFTR---Na and Cl- movement

and reabsoprtion into lumen impeded and reabsoprtion into lumen impeded

Goodman, B and Percy, WH..CFTR in Teaching Membrane Transport. Adv Physiol Educ. 29 (79-82); 2005

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CF: Diagnostic Methods

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Diagnosis---Sweat Diagnosis---Sweat chloridechloride

Technique first Technique first described by Gibson described by Gibson and Cooke in 1950sand Cooke in 1950s Chemical that Chemical that

stimulates sweating stimulates sweating placed under placed under electrode pad; saline electrode pad; saline under other electrode under other electrode pad on armpad on arm

Mild electric current Mild electric current is passed between is passed between electrodeselectrodes

Sweat collectedSweat collected

http://www.nucleusinc.com Illustration copyright 2003 Nucleus Communications, Inc.

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Sweat chlorideSweat chloride Positive Sweat Positive Sweat

chloride: 60-165 meq/L chloride: 60-165 meq/L Borderine sweat Borderine sweat

chloride: 40-60 meq/L chloride: 40-60 meq/L Normal sweat chloride: Normal sweat chloride:

0-400-40

False positives:False positives: HypothyroidismHypothyroidism Addison diseaseAddison disease Ectodermal dysplasiaEctodermal dysplasia Glycogen storage Glycogen storage

diseasedisease EdemaEdema MalnutritionMalnutrition Lab error (evaporation Lab error (evaporation

or contamination of or contamination of sample)sample)

False negatives:False negatives: EdemaEdema MalnutritionMalnutrition Some CF mutationsSome CF mutations Sample dilutedSample diluted

Davis, P. Cystic Fibrosis Since 1938. AJRCCM Articles in Press.

Doi: 10.1164/rccm.200505-840OE; 2005.

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Genetic testingGenetic testing

Mutation analysis availableMutation analysis available Varies from screening for most common Varies from screening for most common

mutations to sequencing entire CFTR mutations to sequencing entire CFTR genegene

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Prenatal screeningPrenatal screening

American College of Obstetricians and American College of Obstetricians and Gynecologists recommended offering Gynecologists recommended offering patients option of prenatal screening for patients option of prenatal screening for CFCF Carrier testing of 23 most common Carrier testing of 23 most common

mutationsmutations Sensitivity of prenatal screening for CF Sensitivity of prenatal screening for CF

among the white population among the white population <<78%78%11

lower than that for newborn screening lower than that for newborn screening sensitivity of prenatal testing in racial and ethnic sensitivity of prenatal testing in racial and ethnic

minority populations is lowerminority populations is lower11

1. Grosse et al. Newborn Screening for Cystic Fibrosis. MMWR.53 (RR13):1-36; 2004.

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Newborn Screening for Newborn Screening for CFCF

Goal: diagnose early---evidence that Goal: diagnose early---evidence that early diagnosis may be associated early diagnosis may be associated with better nutritional outcome and with better nutritional outcome and chest radiographic scoreschest radiographic scores11

Several different protocols in Several different protocols in different statesdifferent states Immunoreactive trypsinogen usually first Immunoreactive trypsinogen usually first

followed by either sweat or DNA testingfollowed by either sweat or DNA testing

1. Mérelle ME, Nagelkerke AF, Lees CM, Dezateux C. Newborn screening for

cystic fibrosis. Cochrane Database of Systematic Reviews. Issue3; 2005.

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Cystic fibrosis---TreatmentCystic fibrosis---TreatmentMultidisciplinaryMultidisciplinary

Airway ClearanceAirway Clearance InfectionInfection NutritionNutrition Gastrointestinal Gastrointestinal InflammationInflammation InfertilityInfertility Social IssuesSocial Issues

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Treatment: Pulmonary Treatment: Pulmonary toilet/Airway clearancetoilet/Airway clearance

Chest physiotherapyChest physiotherapy Postural drainage and percussionPostural drainage and percussion P.E.P valve, Acapella valve, Flutter valveP.E.P valve, Acapella valve, Flutter valve High frequency chest wall oscillationHigh frequency chest wall oscillation

AlbuterolAlbuterol BronchodilationBronchodilation Increase ciliary efficiencyIncrease ciliary efficiency

Dornase alpha/recombinant DNaseDornase alpha/recombinant DNase Hypertonic Saline by nebulizationHypertonic Saline by nebulization

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Treatment: Chronic Treatment: Chronic infectioninfection

Inhaled antibioticsInhaled antibiotics Inhaled tobramycin in patients with pseudomonasInhaled tobramycin in patients with pseudomonas

Sputum cultures Sputum cultures Treatment of pulmonary exacerbationTreatment of pulmonary exacerbation

Pulmonary exacerbation---change in symptoms Pulmonary exacerbation---change in symptoms and signs from baseline (cough, sputum and signs from baseline (cough, sputum production, lung function, increased crackles on production, lung function, increased crackles on physical exam)physical exam)

Requires hospitalization for antibiotics IV, as well Requires hospitalization for antibiotics IV, as well as increased airway clearanceas increased airway clearance

Cystic Fibrosis Foundation. Clinical Practice Guidelines for Cystic fibrosis.1997.

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Treatment: Anti-Treatment: Anti-inflammatory agentsinflammatory agents

IbuprofenIbuprofen Konstan et al., 2003Konstan et al., 2003 85 patients 5-39 years of age with mild 85 patients 5-39 years of age with mild

lung disease randomized to placebo or lung disease randomized to placebo or high dose ibuprofen over 4 yearshigh dose ibuprofen over 4 years

Ibuprofen group:Ibuprofen group: Slower decrease in FEV1 annually than placebo Slower decrease in FEV1 annually than placebo

group; better weight maintenance group; better weight maintenance No difference in frequency of hospitalization No difference in frequency of hospitalization Best effect seen in patients less than 13 years of Best effect seen in patients less than 13 years of

age age

Konstan et al., Effect of High Dose Ibuprofen in Patients with Cystic Fibrosis. NEJM. 332:848-54; 2003.

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Treatment: AzithromycinTreatment: Azithromycin

Saiman et al., 2003 double blind Saiman et al., 2003 double blind placebo controlled trial of placebo controlled trial of azithromycinazithromycin 185 patients randomized to receive 3 185 patients randomized to receive 3

times weekly azithromycin or placebotimes weekly azithromycin or placebo Improvements in lung function, weight, Improvements in lung function, weight,

and number of pulmonary and number of pulmonary exacerbations (decreased courses of exacerbations (decreased courses of antibiotics and days in hospital)antibiotics and days in hospital)

Saiman et al., Azithromycin in Patinets with Cystic Fibrosis Chronically Infected with Pseudomonas Aeruginosa. JAMA 290(13):1749; 2003.

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Treatment: Nutrition Treatment: Nutrition

Follow nutrition parameters closelyFollow nutrition parameters closely Pancreatic enzymesPancreatic enzymes Vitamin supplementationVitamin supplementation Other nutritional supplementationOther nutritional supplementation

Tube feedingsTube feedings High calorie supplemental shakes, High calorie supplemental shakes,

formulasformulas

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Nutrition parametersNutrition parameters Percent ideal body weight (IBW%)Percent ideal body weight (IBW%)

90-110%: Normal90-110%: Normal 85-89%: Underweight85-89%: Underweight 80-84%: Mild malnutrition80-84%: Mild malnutrition 75-79%: Moderate malnutrition75-79%: Moderate malnutrition <75%: Severe malnutrition<75%: Severe malnutrition

Height as a percentage of 50Height as a percentage of 50thth percentile percentile height for age (height/50height for age (height/50thth percentile height percentile height for age )X100.for age )X100. 95-100% normal95-100% normal 90-94%: mildly stunted90-94%: mildly stunted 85-89%: moderately stunted85-89%: moderately stunted <85%: severely stunted<85%: severely stunted

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Treatment: Pancreatic Treatment: Pancreatic enzymesenzymes

Initiate if have malabsorption historyInitiate if have malabsorption history Fecal fatFecal fat Fecal elastaseFecal elastase

May need H2 blocker or PPI to May need H2 blocker or PPI to activate enteric coated enzymeactivate enteric coated enzyme

Fibrosing colonopathyFibrosing colonopathy Strictures in the colon associated with Strictures in the colon associated with

high dose enzyme use (enzyme gets to high dose enzyme use (enzyme gets to colon and causes damage leading to colon and causes damage leading to scarring/stricture)scarring/stricture)

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Treatment: Cystic fibrosis Treatment: Cystic fibrosis related liver diseaserelated liver disease

UrsodiolUrsodiol Increased bile flowIncreased bile flow Decrease toxicity of bile acidsDecrease toxicity of bile acids

Sclerotherapy, portosystemic shuntsSclerotherapy, portosystemic shunts Liver transplantation---only curative Liver transplantation---only curative

treatment for portal hypertensiontreatment for portal hypertension

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Treatment: InfertilityTreatment: Infertility

Microsurgical epididymal sperm Microsurgical epididymal sperm aspiration coupled plus aspiration coupled plus in vitroin vitro technology technology

Percutaneous epididymal sperm Percutaneous epididymal sperm aspirationaspiration

Testicular sperm extractionTesticular sperm extraction Maternal genetic testing Maternal genetic testing

McCallum, TJ et al., Fertility in men with cystic fibrosis. Chest 118:1059-1062; 2000.

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Psychosocial issuesPsychosocial issues

Quality of lifeQuality of life Frequent hospitalizationsFrequent hospitalizations Time spent on therapiesTime spent on therapies Morbidity from diseaseMorbidity from disease Restrictions secondary to diseaseRestrictions secondary to disease

Adherence to therapiesAdherence to therapies Family planningFamily planning End of life issuesEnd of life issues

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““It is, in fact, nothing short of a It is, in fact, nothing short of a miracle that the modern methods of miracle that the modern methods of

instruction have not entirely instruction have not entirely strangled the holy curiosity of strangled the holy curiosity of

inquiry.”inquiry.”----Albert Einstein----Albert Einstein