Day 8, Lecture 3 (Aug 31): Clinical Correlation 2: Cystic Fibrosis

Question 1

Mode of transmission of Cystic fibrosis

Answer 1

• Autosomal recessive
  
  • mutations of a gene located on chromosome 7 called the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)
  • CFTR protein is a cAMP-regulated chloride channel that usually resides within the apical portion of mucosal epithelial cells
  • Most common mutations- DeltaF508, G542X, G551D, W1282X, W1303K, and R 553X

Question 2

___ mortality in CF is a result of lung disease

Answer 2

85%

Question 3

Question 4

THe CFTR gene is on what chromosome

Answer 4

Chromosome 7

Question 5

A normal-functioning CFTR channel moves ______ while a mutant CFTR channel does not, thus causing ______

Answer 5

chloride ions to the outside of the cell while a mutant CFTR channel does not, causing sticky mucus to build up on the outside of the cell

Question 6

Classes of cystic fibrosis-causing mutations

Answer 6

Question 7

Newborn screen for CF

Answer 7

• A few drops of blood from a heel prick are placed on a special card, called a Guthrie card.
• IRT level: >65ng/dl

Question 8

What steps are taken if a newborn has a hellp prick IRT level: >65 ng/dl

Answer 8

Question 9

Why does the sweat test help determine CF

Answer 9

• Malfunction of CFTR in sweat glands leads to the inability to reabsorb water and thus dehydration
• this leads to sweat having a higher than normal concentration of sodium and chloride

Question 10

What are the primary goals of CF

Answer 10

1. Maintain lung function
2. Reduce pulmonary exacerbations
3. Improve nutritional status

Question 11

What is the most prevalent bacterial infections for CF patients

Answer 11

• P. aeruginosa

Question 12

What are the most difficult/complex bacterial infections to eradicate in CF patients

Answer 12

• Ps. aeruginosa and B. cepacia
  
  • ​True infection, not “colonization”
    
    • ​difficulty in eradicating due too:
      
      • intrinsic antibiotic resistance
      • Acquired antibiotic resistance
      • Poor antibiotic penetration into secretions
      • Alginate produced by mucoid Ps. (biofilms)
      • CF-related defects in mucosal (but not systemic) defenses

Question 13

What is the most reconized hallmark in CF disease

Answer 13

• progressive obstructive lung disease
  
  • early thickening of progressive mucus
  • subsequent colonization with pathogenic bacteria
  • Ultimately diffuse airway inflammation that destroys conducting airways and lung parenchyma
  • Combination of:
    
    • Dessicated mucosal suface, infection, and host’s inflammatory response leads to inspissation of airway debris and progressive endobronchial destruction

Question 14

Symptoms of CF

Answer 14

• Couch, sputum production
• Tachypnea
• use of accessory muscles
• Increased AP diameter of chest
• Hypoxemia
• Exercise intolerance
• Coarse crackles
• Decreased or absent breath sounds/air movement
• Decreased pulmonary function
• Weight loss

Question 15

What is the strongest predictor of mortality in CF

Answer 15

• FEV₁ (forced expiratory volume)

Question 16

almost half of the CF patients are homozygous for

Answer 16

F508del-CFTR

Question 17

F508del-CFTR

Answer 17

• Almost half of CF patients are homozygous for F508del-CFTR
• Severe phenotype
• early onset of progressive lung disease
• Shortened life expectancy compared to overall CF population

Question 18

Pulmonary exacerbations in CF patients

Answer 18

• Serious life events for a CF patient
• Occur and increase throughout the life of a CF patient
• Characterized by worsening respiratory symptoms (cough, sputum, production, shortness of breath)
  
  • Typically require treatment with antibiotics
  • Often result in hospitalization (average of 19 days/year), absence from school or work
• Major clinical consequences
  
  • Irreversible and progressive loss of lung function
  • Increased risk for future exacerbations
  • reduced health-related quality of life
  • increased risk of deat

Question 19

The underlying cause of CF is

Answer 19

• loss of CFTR protein activity
  
  • Reduced CFTR activity results in a loss of chloride transport causing abnormalities in tissues where CFTR protein is present

Question 20

Respiratory therapies in CF are directed at?

Answer 20

• Inflammation
• Infection

Question 21

What causes infections in the airways of CF patients

Answer 21

Question 22

Question 23

Question 24

What are some of the therapies that help combat the effects of neutrophils attacking bacterial infections in CF patients lungs

Answer 24

Question 25

Why is Pulmozyme used to treat CF?

Answer 25

is is a Dnase and is used to breakdown the DNA matrixes of the white blood cells in the lung tissue. This is used becasue without the enzyme the DNA will incorporate into the mucus and make it thicker

Question 26

What are some therapies of CF that help with mucus clearing?

Answer 26

* Clearance techniques and vests are also used

Question 27

What is Kalydeco/Ivacaftor used for in treatment of CF

Answer 27

* Re-establish Chloride transport via the CFTR protein. * IVacaftor is aCFTR potentiator that facilitates increased chloride transport by potentiating the channel-open probability (or gating) of the CFTR protein at the cell at the surface * thus resulting in more normal function of the cilia and mucus layer combined with physical removal of mucus form the airway relieves physical obstruction and helps clear bacteria form the airways * Restoring CFTR function results in improved FEV

Question 28

Therapies for the treatment of chronic airway infections in CF patients

Answer 28

*

Question 29

do current therapies treat the underlying cause of CF

Answer 29

* No!

Question 30

\_\_\_\_\_ treat the underlying cause of CF

Answer 30

* CFTR modulators

Question 31

New CFTR modulator for homozygous F508del CF patients?

Answer 31

* Lumacaftor * improves the conformational stability of F508del-CFTR, resulting in increased processing and trafficking of mature CFTR protein to the cell surface * This drug is used with ivacaftor

Question 32

Nutritional status is poor in CF patients because

Answer 32

* common due to pancreatic insufficiency and malabsorption * Lower body mass index (BMI) is associated with reduced lung function * Poor nutritional status is a predictor of reduced survival

Question 33

GI issues in CF patients

Answer 33

* Protein and Fat malabsorption * Malnutrition/failure ot thrive * Meconium ileus * Distal intestinal obstruction syndrome * Obstructive jaundice * Focal biliary cirrhosis * Rectal prolapse * Recurrent pancreatitis

Question 34

Besides lung and GI issues other notable manifestations in CF include

Answer 34

* DM * Digital clubbing * Hyponatremic dehydration * Hypochloremic alkalosis * Vitamin A, D, E, and K deficiences * Zinc deficiency dermatitis * Male infertility * Anxiety * Depression

Question 35

Recommended timing for transitioning CF patients to adult care

Answer 35

* 18-21 years old

Question 36

Question 37

What is the median number of therapies and mean time need to complete the therapies for adult CF patients?

Answer 37

* 7 therapies per day * mean time: 108 minutes

Question 38

Life expectancy for CF patients

Answer 38

41 years old