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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 disease, pancreatic insufficiency, elevation of sweat electrolytes and male infertility

Genetics of CFMost common lethal genetic disease in Causasians

30,000 affected individuals in US27,000 in Europe

CFTR - cAMP regulated chloride channel located in apical membrane of glandular epithelium – Long arm of chromosome #7

D508 most common mutation1000 identified mutations

– Encodes for a protein of 1480 amino acids– Defective ion transport

“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”

Presentation(CF PANCREAS)

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

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CFTR

Abnormalities in the CFTR protein change the constituents of mucous and result in abnormal reabsorption of water, creating thickened mucus and inadequate mucociliary function.The CF airway has many changes leading to mucous plugging, chronic infection, and inflammation.

CFTR

Hypothesis

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 Airway

Used with permission - R. Gibson, 2004.

Neutrophils

Bacteria

Muc

us

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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 PluggingInfection

Inflammation

MorbidityMortality

AbnormalCFTR

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Airway Mucous Plugging, Infection, and Inflammation in

Cystic Fibrosis

Used with permission – J. Wagener, 2004.

0

20

40

60

80

100

Age (y)

Total Cultures

(%)

Major Airway Pathogens by Patient 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 inflammation in BALF of infants

with 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 Bronchoalveolar Lavage Fluid from Cystic Fibrosis

Patients

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: End-Stage Bronchiectasis

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CF Lung Function

Lung function in CF

A-a gradientcomplianceflow rates at low lung volumesslope of phase III nitrogen washoutphysiologic dead spaceexercise tolerance

Signs and Symptoms of Pulmonary Exacerbation

Increased coughIncreased sputumWeight lossSchool/work absenteeismIncreased dyspnea

New chest findings– rales, wheezes

Decreased exercise toleranceDecreased FEV1– down 10%

New radiographic findings

CF mild disease

Bronchiectasis

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

Used with permission - C. Milla, 2004.

CF Pneumothorax

BLEBS

CF: Pulmonary Complications

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Exacerbations Contribute to the Deterioration 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 management

Regular visits to CF CenterAirway clearanceMucus thinners (DNase, hypertonic saline)Antibiotics( PO-IV-Aerosol)Anti inflammatory drugs

Airway Clearance

CPTVestFlutterACB

RefluxRisk factor for PaAdherence

ISSUES

CF Flutter

Anti-inflammatory Rx

Steroids– inhaled v oral

IbuprofenMacrolides

SafetyAdherence? Delay in progression of the disease

ISSUES

Diffuse Pan-bronchiolitis (DPB)

DPB clinically resembles CF– More common in Japan than in Western countries – Age of onset between 30 and 60 years of age

Chronic lower respiratory tract infection– Neutrophils predominant inflammatory cell – H. influenzae and S. pneumonia early in disease – P. aeruginosa major pathogen later

70% of patients have mucoid strains– Progress to bronchiectasis and respiratory failure

Pancreatic insufficiency not a 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%

DNase

Recombinant DNaseHydrolyzes DNAAerosolized

Treating Airway infections

Prophylactic treatment– prevent colonization

Exacerbations– improves lung function– reduces inflammation– decreases bacterial density

First isolates– may delay colonization

Antibiotics

OralIVAerosolizedSpecial Considerations:– Volume of distribution– Sensitivities– Drug Interactions– Side effects

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CF PFT’s

CF: Gastrointestinal Disease

Pancreatic insufficiency/malabsorptionLipo-soluble vitamin deficiencyFailure to thriveNeonatal intestinal obstruction (15%)Recurrent distal intestinal obstructionBiliary stasis

CF: Pancreas-malabsorption

Nutrition 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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SUMMARY

Need to understand the pathophysiology of CF lung disease in young patientsNeed to understand the risk/benefit ratio of new treatmentsAdherenceWindow of opportunityChanging landscape