CF?

Question 1

What is CF?

Answer 1

1. Most common lethal genetic disorder.
2. Lung dysfunction and infection most common cause morbidity.
3. Neutrophilic inflammation.

Question 2

How is CF screened for?

Answer 2

Immunoreactive trypsinogen (IRT) - Guthrie test. 
Trypsinogen is made by the pancreas and secreted into the gut. This secretion is impaired in CF. 
Hence, elevated blood levels are detected by the Guthrie test. 

Sweat test: Elevated skin Cl- levels.

Question 3

Skin Cl- levels of above what indicate a likely positive CF result?

Answer 3

Above 60mM

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

Question 4

What are the structural changes associated with CF lung disease?

Answer 4

1. Bronchial wall thickening
2. Bronchoiectasis: Abnormal dilation of the bronchial tree
3. Pneumothorax

Question 5

Why is there a massive neutrophil infiltration into the airways of Cystic Fibrosis sufferers?

Answer 5

There is an inability to clear away mucus so mucus plugging occurs.
Frustrated phagocytosis and a failure to clear bacteria and dying neutrophils.

Question 6

What is the CFTR?

Answer 6

Cystic Fibrosis Transmembrane conductance regulator.

Question 7

What is CF caused by?

Answer 7

The presence of mutations in both copies of the gene for the CFTR protein.
When this malfunction occurs secretions which are supposed to be thin are thick.

Question 8

Why are biofilms a problem in CF?

Answer 8

They are hard to treat with antibiotics and form easily in the thick mucus found in the lungs of CF patients.

Pseudomonas aeruginosa comes to dominate.

Question 9

How does the abnormal bronchial dilation in CF contribute to chronic infections?

Answer 9

Low volume of air/slow flow as a result of dilation leads to thicker than usual mucus, more viscous.

Difficult for the cilia to clear and provides a growth environment for bacteria.

Partial correction can occur via inhaled hypertonic saline.

Question 10

Why are there high levels of DNA in the sputum of CF patients?

Answer 10

Dying neutrophils attempting to clear bacteria are unable to clear bacteria from the viscous mucus and accumulate.

Question 11

Why does non-functioning CFTR lead to thick mucus?

Answer 11

Normally the efflux of chlorine out of the epithelium would cause water to following down a concentration gradient resulting in less thick mucus.

Normal: 7micrometer ASL
CF: 1micometer ASL

Question 12

What bacterial infections are common in CF patients?

Answer 12

Lung infections caused by:
P. Aeruginosa (predominantly)
S. aureus 
H. Influenza 
B. cepacia

Question 13

When would fluoxacillin be used in CF patients?

Answer 13

As prophylaxis of a S. aureus infection in infants.

Question 14

What is the therapeutic approach for Class I (nonsense mutations) CF?

Answer 14

PTC suppressors.
Ataluren
Aminoglycosides.

Question 15

What is the therapeutic approach for Class II CF?

Answer 15

Correctors and potentiators:
Lumacaftor
VX- 661
Ivacaftor

Question 16

What is the therapeutic approach for Class III CF?

Answer 16

Potentiators:

Ivacaftor

Question 17

What is the therapeutic approach for Class IV CF?

Answer 17

Potentiators:

Ivacaftor

Question 18

How does Ataluren function?

Answer 18

Class I treatment targeting protein synthesis:

Ataluren forces read-through of premature termination codon.

Question 19

How does Lumacaftor function?

Answer 19

Acts as a chaperone during protein folding and increases the number of CFTR proteins that are trafficked to the cell surface

Question 20

How does Ivacaftor function?

Answer 20

Ivacaftor, a CFTR potentiator, improves the transport of chloride through the ion channel by binding to the channels directly to induce a non-conventional mode of gating which in turn increases the probability that the channel is open.

Question 21

How does Amiloride function?

Answer 21

Blocks ENaC.
Very short half-life in airway.
New compounds may be more effective but come with a hyperkalaemia risk.
NO ADDED BENEFIT.

Question 22

Class I treatment targeting protein synthesis

Answer 22

Ataluren forces read-through of premature termination codon.

Question 23

How does Denufosol function?

Answer 23

Denufosol is an agonist at the P2Y2 subtype of purinergic receptors, an alternative chloride channel. Activating this alternate chloride channel theoretically increases ion transport in cystic fibrosis patients which compensates the effects caused by the non-functioning CFTR.

“Calcium-activated chloride channel [CACC] activators”

*Risk of ENHANCING mucus secretion by activating goblet cells”

Question 24

Why are high dose NSAIDS used?

Answer 24

Ibuprofen

Some slowing of lung function decline.

Question 25

Acts as a chaperone during protein folding and increases the number of CFTR proteins that are trafficked to the cell surface

Answer 25

Lumacaftor

Question 26

Improves the transport of chloride through the ion channel by binding to the channels directly to induce a non-conventional mode of gating which in turn increases the probability that the channel is open.

Answer 26

Ivacaftor

Question 27

An agonist at the P2Y2 subtype of purinergic receptors, an alternative chloride channel. Activating this alternate chloride channel theoretically increases ion transport in cystic fibrosis patients which compensates the effects caused by the non-functioning CFTR.

Answer 27

Denufosol.

*Risk of ENHANCING mucus secretion by activating goblet cells”

Question 28

Are glucocorticoids useful in CF management?

Answer 28

No proof that inhalation leads to reduction in inflammation.
IV Prednisolone may provide some benefit but comes with significant adverse effects:
impaired growth, cataracts.

Question 29

What macrolide may be of benefit in CF management?

Answer 29

Azithromycin.
No direct antibiotic action against P. aeruginosa.
Not sure how it works.

Question 30

What can we use to breakdown mucus?

Answer 30

DNAse

Question 31

How can we hydrate the mucus?

Answer 31

Hypertonic saline, Mannitol.