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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

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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””

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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.

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CFTRCFTR

HypothesisHypothesis

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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

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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.

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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

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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

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CF mild diseaseCF mild disease

Bronchiectasis

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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

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BLEBSBLEBS

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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

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Airway ClearanceAirway Clearance

CPTCPTVestVestFlutterFlutterACBACB

RefluxRefluxRisk factor for Risk factor for PaPaAdherenceAdherence

ISSUES

CF FlutterCF Flutter

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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

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Treating Airway infectionsTreating Airway infections

Prophylactic treatmentProphylactic treatment–– prevent colonizationprevent colonization

ExacerbationsExacerbations–– improves lung functionimproves lung function–– reduces inflammationreduces inflammation–– decreases bacterial densitydecreases bacterial density

First isolatesFirst isolates–– may delay colonizationmay delay colonization

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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

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CF: PancreasCF: Pancreas--malabsorptionmalabsorption

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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