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CYSTIC FIBROSIS

Lynne M. Quittell, M.D.Director, CF CenterColumbia University

What is Cystic Fibrosis?

Chronic, progressive and life limiting autosomal recessive genetic disease characterized by chronic respiratory di ti i ffi idisease, pancreatic insufficiency, elevation of sweat electrolytes and male infertility

“Wehe dem Kind, das beim Kuss auf die Stirn salzig

schmekt, er ist verhext und muss bald sterben”

“Woe is the child who tastes salty from a kiss on the brow, for he is cursed , and soon must die”

Genetics of CF• Most common lethal genetic disease in

Causasians30,000 affected individuals in US27,000 in Europe

• CFTR - cAMP regulated chloride channelCFTR cAMP regulated chloride channel located in apical membrane of glandular epithelium – Encodes for a protein of 1480 amino acids– Defective ion transport– Long arm of chromosome #7

• D508 most common mutation• > 1500 identified mutations

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Ion Transport

LysozymeLactoferin, SLPI

Phospho lipase A2Secretory IgA

SP-A, SP-D, NOhBD 1 hBD 2 LL 3Phagocytic

MucociliaryClearance

Mucus

The Cystic Fibrosis AirwayBacteria

hBD-1, hBD-2, LL-3

Cl-Na+

PhagocyticCells Cl-

Na+CFTR

AcquiredImmunity

Plug

NFκβIL-8

Used with permission - R. Gibson, 2004.

Neutrophils

Muc

us

3

The sweat test ( Chloride)

NormalUnder 40 mEq/L

Borderline40-60 mEq/L

PositiveOver 60 mEq/L

CF: Pulmonary Disease Pathogenesis of Cystic Fibrosis Lung Disease

CF Gene

Mucous PluggingAbnormal Infection

Inflammation

MorbidityMortality

AbnormalCFTR

Presentation(CF PANCREAS)

C Chronic respiratory diseaseF Failure to thriveP PolypsA Alkalosis metabolicA Alkalosis, metabolicN Neonatal intestinal obstructionC Clubbing of fingersR Rectal prolapseE Electrolyte in sweatA Aspermia / absent vas deferensS Sputum – S.aureus/P.aeruginosa

Airway Mucous Plugging, Infection, and Inflammation in

Cystic Fibrosis

Used with permission – J. Wagener, 2004.

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Age Specific Prevalence of Respiratory Infectionsin CF Patients

40

60

80

100

P. aeruginosa

S. aureus

H i fl

0

20

0 to 1 2 to 5 6 to 10 11 to 17 18 to 24 25 to 34 35 to 44 45+

Age (Years)

P. aeruginosa 56.4% H. influenza 17.0% B. cepacia Complex 3.1%

S. aureus 51.8% S. maltophilia 12.3% MRSA 17.2%

MRSA H. influenza

S. maltophilia B. cepacia

Evidence of increased inflammation in BALF of infants

with CF

60

80

20

25Controls

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% Neutrophils

0

5

10

15 IL-8 (ng/ml)

CF Lung: End-Stage Bronchiectasis

23

1

CF Lung Function

5

Signs and Symptoms of Pulmonary Exacerbation

• Increased cough• Increased sputum• Weight loss• School/work

• New chest findings– rales, wheezes

• Decreased exercise tolerance• School/work

absenteeism• Increased dyspnea

• Decreased FEV1– down 10%

• New radiographic findings

CF mild disease: CF mild disease: hyperinflation, increased hyperinflation, increased markings markings

CF advanced disease: with bronchiectasis

High-Resolution Inspiratory and Expiratory CT Scan in 12 year old

Used with permission - C. Milla, 2004.

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CF: Pulmonary Complications CF: Respiratory management

• Regular visits to CF Center• Airway clearance• Mucus thinners (DNase,

h t i li )hypertonic saline)• Antibiotics( PO-IV-Aerosol)• Anti inflammatory agents

Airway Clearance

• CPT• Vest• Flutter • Reflux

ISSUES

• Flutter• ACB

Reflux• Adherence

Airway Clearance• Chest Physical therapy• Vest – mechanical percussion• Flutter, Acapella • Breathing techniques : ACB• Exercise

Mucolytic agents

• Recombinant DNase• Hypertonic saline

Treating Airway infections

• Prophylactic treatment– prevent colonization

• Exacerbationsi l f ti– improves lung function

– reduces inflammation– decreases bacterial density

• First isolates– may delay colonization

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Antibiotics

• Oral• IV• Aerosolized• Special Considerations:

– Volume of distribution– Sensitivities– Drug Interactions– Side effects

Anti-inflammatory Rx

• Steroids– inhaled v oral

• Ibuprofen• Macrolides

• Safety• Adherence• ? Delay in

ISSUES

Macrolides • ? Delay in progression of the disease

Relative Change in FEV1 % Predicted

2

4

5

Azithromycin

Day 168 Treatment Effect:6.21% (p=0.001)

Day 168 Δ: 4.44%

0 28 84 168 196

-4

-2

0

Study Day

Placebo Day 168 Δ : -1.77%

CF PFT’s CF: Gastrointestinal Disease

• Pancreatic insufficiency/malabsorption• Lipo-soluble vitamin deficiency• Failure to thrive• Neonatal intestinal obstruction (15%)• Recurrent distal intestinal obstruction• Biliary stasis

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CF: Pancreas-malabsorption

Median Predicted Survival Age, 1985-2005(with 95 percent confidence bounds)

32

34

36

38

40

Surv

ival

Age

(Yea

rs)

24

26

28

30

'85 '86 '87 '88 '89 '90 '91 '92 '93 '94 '95 '96 '97 '98 '99 '00 '01 '02 '03 '04

Year

Med

ian

S

'05

As of August 2006, the median predicted survival is 36.5 years

for 2005.

SUMMARY

• Need to understand the pathophysiology of CF lung disease in young patients

• Need to understand the risk/benefit ratio of new treatmentsnew treatments

• Adherence• Window of opportunity• Changing landscape