CYSTIC FIBROSIS Lynne M. Quittell, M.D. Director, CF Center - - PDF document

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Jan 13, 2024 453 likes •696 views

CYSTIC FIBROSIS Lynne M. Quittell, M.D. Director, CF Center Columbia University What is Cystic Fibrosis? Chronic, progressive and life limiting autosomal recessive genetic disease characterized by chronic respiratory disease, pancreatic

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CYSTIC FIBROSIS

Lynne M. Quittell, M.D. Director, CF Center Columbia 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 l i f tilit male infertility

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“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 from a kiss on the brow, for he is cursed , and soon must die”

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Genetics of CF

Most common lethal genetic disease in

Causasians 30,000 affected individuals in US

27,000 in Europe

CFTR - cAMP regulated chloride channel

located in apical membrane of glandular epithelium

– Encodes for a protein of 1480 amino acids p – Defective ion transport – Long arm of chromosome #7

D508 most common mutation
> 1500 identified mutations

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Ion Transport

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L Mucociliary Clearance

The Cystic Fibrosis Airway

Bacteria Lysozyme Lactoferin, SLPI Phospholipase A2 Secretory IgA SP-A, SP-D, NO hBD-1, hBD-2, LL-3 Phagocytic Cells Cl- Na+ CFTR Clearance Mucus Plug Cl-Na+ Acquired Immunity NFκβ IL-8 Used with permission - R. Gibson, 2004. Neutrophils Mucus

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The sweat test ( Chloride)

Normal Normal Under 40 mEq/L Borderline 40-60 mEq/L Positive Over 60 mEq/L

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CF: Pulmonary Disease Pathogenesis of Cystic Fibrosis Lung Disease

CF Gene Mucous Plugging Infection Inflammation Abnormal CFTR Morbidity Mortality

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Presentation (CF PANCREAS)

C Chronic respiratory disease F F il t th i F Failure to thrive P

Polyps A Alkalosis, metabolic N Neonatal intestinal obstruction C Clubbing of fingers R Rectal prolapse E Electrolyte in sweat A Aspermia / absent vas deferens S Sputum – S.aureus/P.aeruginosa

Airway Mucous Plugging, Infection, and Inflammation in Cystic Fibrosis

Used with permission – J. Wagener, 2004.

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10 Age Specific Prevalence of Respiratory Infections in CF Patients

80 100

P. aeruginosa

20 40 60

S. aureus

MRSA

H. influenza
S. maltophilia
B. cepacia

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%

Evidence of increased inflammation in BALF of infants with CF

2 CF 20 40 60 80 % Neutrophils 10 15 20 25 IL-8 (ng/ml) Controls

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

20 5

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CF Lung: End-Stage Bronchiectasis

1 2 3

CF Lung Function

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Signs and Symptoms of Pulmonary Exacerbation

Increased cough

I d t

New chest findings

rales wheezes

Increased sputum
Weight loss
School/work

absenteeism

Increased dyspnea

– rales, wheezes

Decreased exercise

tolerance

Decreased FEV1

– down 10%

New radiographic

findings

CF mild disease: CF mild disease: hyperinflation, increased hyperinflation, increased markings markings CF advanced disease: with bronchiectasis

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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,

hypertonic saline)

Antibiotics( PO-IV-Aerosol)
Anti inflammatory agents

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Airway Clearance

CPT
Vest
Flutter
ACB
Reflux
Adherence

ISSUES

Airway Clearance

Chest Physical therapy
Vest – mechanical percussion

p

Flutter, Acapella
Breathing techniques : ACB
Exercise

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Mucolytic agents

Recombinant DNase
Hypertonic saline

Treating Airway infections

Prophylactic treatment

– prevent colonization

Exacerbations

– improves lung function – reduces inflammation decreases bacterial density – 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

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Anti-inflammatory Rx

Steroids

inhaled v oral

S f t

ISSUES – inhaled v oral

Ibuprofen
Macrolides
Safety
Adherence
? Delay in

progression of the disease

Relative Change in FEV1 % Predicted

4 5

Day 168 Treatment Effect: 6.21% (p=0.001) Day 168 Δ: 4.44%

Azithromycin Placebo

Day 168 Δ :

1.77%

28 84 168 196

Study Day

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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

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23 Median Predicted Survival Age, 1985-2005

(with 95 percent confidence bounds)

36 38 40

e (Years)

26 28 30 32 34

Median Survival Age

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

Year

'05

As of August 2006, the median predicted survival is 36.5 years for 2005.

SUMMARY

Need to understand the pathophysiology

f CF l di i ti t

f CF lung disease in young patients
Need to understand the risk/benefit ratio of

new treatments

Adherence

Window of opportunity

Window of opportunity
Changing landscape