Respiratory Disease (1) Cystic Fibrosis

Question 1

Pathophysiology Overview

Answer 1

• Ion conductance abnormalities

- Thick sticky mucus
>Malnutrition
>Frequent respiratory infections
>Breathing difficulties
>Permanent lung damage

(In healthy lungs, mucus forms gel-like protective barrier)

Question 2

Pathophysiology (GIT)

Answer 2

• Pancreatic insufficiency
• Gastrointestinal symptoms
  >Frequent diarrhoea
  >Bulky or foul smelling stools
  >Excessive appetite, but poor weight gain
  >Meconium ileum (obstruction of bowel at birth)
  >Distal intestinal obstruction syndrome

Question 3

Pathophysiology (Respiratory)

Answer 3

• Compromised mucocilary clearance
• Lung inflammation
• Lung infection
  >Haemophilus influenza
  >Staphylococcus aureus
  >Pseudomonas aeruginosa
• Induction of cytokines
• Amplifying cycle of infection, inflammation & mucus secretion

> > > > Bronchiectasis
Pulmonary insufficiency
Death

Question 4

Colonisation with pathogens impairs lung function

Answer 4

• Percent Predicted FEV1 drops to 60% by 18-24yrs, stays around that level till 45+
• S. aureus and H. Influenzae common in childhood, but infection rates drop over time
• P. Aeruginosa Low infection rates in childhood, but rise significantly over time to 80% by adulthood (18-24yrs)

Question 5

Vicious cycle of chronic airway inflammation

Answer 5

1) P. Aeruginosa products cause neutrophil death
>when apoptotic cells not rapidly cleared
>necrosis ensues

2) Proteases are released
>cause inflammation and
>tissue damage
>also cleaves (3)

3) CXCR1 (chemokine receptor) from the surface of any viable neutrophils

4)This cleavage reduces neutrophil killing of P. Aeruginosa by
>impairing neutrophil responses to IL-8

4)b) At the same time, the cleaved fragments activate TLR2 on epithelial cells
>more inflammation and neutrophil recruitment

5) Result in
>dysregulated chronic inflammatory response
>bacterium is able to persist

Question 6

Pathophysiology (other)

Answer 6

>salty sweat (excessive loss of salt)
>chronic rinosinusitis
>fungal infections with aspergillus
>reflux
>rectal prolapse
>Male infertility (abnormal/absent vans deferens)
>Liver disease
>Osteoporosis
>CF diabetes

Question 7

Genetics

Mendelian Inheritance

Answer 7

Autosomal recessive trait

> child born of two CF carriers 25% likelihood of being afflicted with CF
gene causing cf carried by about 3% of Caucasian population

Question 8

CFTR gene

Answer 8

Gene codes for membrane associated protein known as CFTR

>caused by large single gene located on Chr7 which is known as CFTR

Question 9

CFTR protein

Answer 9

Cl- Ion channel through cellular membrane
>extracellular carbohydrate side chains
>transmembrane regions
>2 ATP binding sites
>1 regulatory domain

Question 10

CFTR gene mutations

Answer 10

Spectrum of mutations that affect its function
>1 in 28 Caucasians carry the most frequently encountered defective gene mutation
>Deletion of phenylalanine at position 508
>ΔF508-CFTR

> > This mutation responsible for about 70% cases worldwide

Question 11

CFTR Mutation Classes

Answer 11

More than 2000 CFTR mutations identified
>categorised in functional classes 1-6

Classes 1-3
>non-functional CFTR protein
>pancreatic insufficiency

Classes 4-6
>some CFTR function
>pancreatic sufficiency

Question 12

CFTR Class 2 Mutation

Answer 12

> Defective trafficking of CFTR to incorrect location
or presentation of non-functional CFTR

> ΔF508 by far most common
70% prevalence
50% homozygous
>major target for CF therapy

Question 13

CFTR Class 3 Mutation

Answer 13

> Defective regulation of the channel opening
G551D mutation
>CFTR protein that is localised on epithelial membrane but fails to open
4% of CF patients

Question 14

Epidemiology

Answer 14

• 80,000 PTs worldwide

- Prevalence
>Europe: 7.4 per 100,000 population
>North America: 1 in 3400 births
>Australia: 1 in 2500 births
>Japan: 1 in 350,000
>India: 1 in 40,000

CF predominantly occurs in white people of Northern European descent

Question 15

Morbidity and Mortality

Answer 15

Once: always fatal
1960s: Median survival <5 years
Mid 1960s: first comprehensive treatment strategy
Today: Life expectancy ~35-39 years

Impact of research on survival
>Pancreatic enzymes
>airway clearance
>antistaphylococcal antibiotics
>antipseufomonal antibiotics
>lung transplant
>DNase
>Inhaled Tobramycin

Question 16

2014: Update on most recent mortality data

Answer 16

Life expectancy of male patients consistently longer than women
>gender gap persists to date

Socioeconomic status, race, ethnicity, ambient air pollution
>found to have significant impact

Access to health insurance is another determinant of survival
>especially a problem in the US

Eventually, 75% succumb to chronic progressive lung disease

Question 17

Cost of healthcare

Answer 17

Prescription drugs, outpatient visits, durable medical equipment
>US$29,718/PT/year (2007)

Since 2015
>CFTR Modulators
>US$250k-300k/PT/Year

Question 18

Diagnosis

Answer 18

Sweat Test
>Measures levels of sodium and chloride in sweat collected on skin
>Repeated chloride values ≥60mmol/L and sodium values ≥70mmol/L are confirmatory

Chest x-rays, lung function test (FEV1), sputum cultures, stool evaluations confirm the diagnosis

Question 19

Screening

Answer 19

Recommended:
>prenatal or preconception carrier screening
>only screens 23 most common mutations

Broad screening kits (up to 97 mutations)
>CFplus
>Tag-It Cystic Fibrosis Kit
>xTAG Cystic Fibrosis 39 Kit v2
>VariantPlex CFTR Kit

Question 20

Prevention

Answer 20

At present, as a disease with a genetic basis, CF cannot be prevented

Until gene therapy to treat the underlying cause becomes available, disease incidence can only be decreased through genetic testing and counselling of prospective parents found to be at risk of transmitting two copies of CFTR

Question 21

Treatment

Answer 21

Depending on stage of disease and organs involved

Daily baseline therapy:
>improve mucus clearance
>decrease inflammation
>control infection
>CFTR protein modulation

> > More aggressive therapy during acute exacerbation
End stage: Lung transplant

Question 22

Drugs:

Antibiotics

Answer 22

Ciprofloxacin hydrochloride (Cipro)
Meropenem (Meronem)

Tobramycin (TOBI)
Colistin sulphae (Promixin)

Aztreonam L-Lysine (cayston)
Levofloxacin (Quinsair)

Question 23

Drugs:

Drugs improving mucociliary clearance

Answer 23

Dornase alpha (Pulmozyme)
Mannitol (Bronchitol)

Question 24

Drugs:

Agents improving CFTR protein function

Answer 24

Ivacaftor (Kalydeco)
Ivacaftor/Lumacaftor (Orkambi)
Ivacaftor/Tezacaftor (Symdeco)

Question 25

Drugs: Agents for pancreatic insufficiency

Answer 25

Pancrelipase (Creon, Zenpep, Pancreaze)

Question 26

Antibacterial Agents Why do we use them?

Answer 26

Defective/Deficient CFTR >Thick sticky mucus buildup in respiratory tracts of CF PTs >>Ideal breeding ground for microorganisms Microorganisms most problematic to CF PTs are virtually innocuous in healthy individuals >P. aeruginosa most common >Gram-negative, nonmotile bacterium >identified in sputum of 80% of all CF patients in mid 20s >near impossible to eradicate ``` Downwards spiral of lung infection >First infection >Inflammation >Recurrent infection >Chronic infection ``` Antibiotic treatment is dependent on severity of infection and isolate

Question 27

Antibiotics: Ciprofloxacin (and meropenem: beta-lactatam antibiotic)

Answer 27

- Quinolone antibiotic - Oral form - Used in mild illness ``` -MOA: >inhibit DNA gyrase >inhibit a type II topoisomerase (Topoisomerase IV) >>necessary to separate bacterial DNA, thereby inhibiting cell division ``` - effectively substitutes one course of IV antibiotics in PTs with mild disease caused by susceptible organisms - May be taken w/wo food as directed by doctor, usually twice a day (every 12 hours) ``` - Side effects >nausea >diarrhoea >dizziness >lightheadedness >headache may occur ```

Question 28

Antibiotics: Tobramycin inhalation solution (TOBI)

Answer 28

- Inhaled aminoglycoside antibiotic for CF - TOBI combats P. Aeruginosa in CF >administered twice daily for 28-day course >effective and well tolerated therapy for early P.aeruginosa infection in PTs with CF >associated with important therapeutic gains in adolescents with CF who normally lose lung function more rapidly than in any other age group - MOA: >binds to site on bacterial 30S and 50S ribosome >prevent formation of 70S complex >mRNA cannot be translated to protein >Cell death >also binds to RNA-aptamers (Artificially created molecules to bind to certain targets)

Question 29

Antibiotics: Levofloxacin

Answer 29

- First fluoroquinolone as inhaled therapy (Oral levofloxacin used for e.g. skin infections but in CF used as inhalation) - Indicated for management of chronic infections with P. Aeruginosa in adult CF patients - Extensive renal elimination - Enhanced penetration into lungs and P.aeruginosa biofilms (high concentrations in sputum and Low serum concentrations) - Comparison: inhaled antibiotic (trobramycin) in 282 participants, showed levofloxacin inhaled was at least as good as Tobramycin at improving FEV1 after 1-3 treatment cycles Rationale: - lower respiratory tract infection with PA is associated with increased morbidity in PTs with CF Objectives: - this study assessed the efficacy and safety of a novel aerosol formulation of levofloxacin in heavily treated CF population with PA infection Nebulised Levofloxacin was well tolerated and demonstrated significant clinical efficacy in heavily treated patients with CF with PA lung infection

Question 30

Agents improving mucociliary clearance DNase alpha Inhalation

Answer 30

- Recombinant human DNase or dornase alpha (Pulmozyme) - Inhaled - Helps thin the mucus in the lungs >coughed out more easily - Most of the DNA is of host origin MCC removes foreign material from lung (defence mechanism) >CF abnormal or insufficient airway clearance Neutrophils play dual role in CF >both anti inflammatory and pro inflammatory effects >In response to bacteria in airways, neutrophils are recruited to lungs to fight infection >WBCs die while fighting >Subsequent decomposition releases their genetic material into mucus >Sticky DNA aggravates the already excessive stickiness of mucus >initiate vicious cycle of further airway obstruction, inflammation and infection - MOA: >recombinant form of human enzyme deoxyribonuclease I (rhDNase) >selectively cleaves DNA and cuts the Long DNA molecules >shorter, less sticky pieces

Question 31

Agents improving mucociliary clearance Mannitol

Answer 31

- Osmotic agent >increases osmolarity of periciliary fluid layer >water moves to lumen (Water from submucosa rehydrates airway surface liquid) >enhancing clearance of mucus - Delivery >dry powder inhalation - Improves mucus clearance and promotes effective coughing - Inhaled dry powder mannitol (Bronchitol) >add-on therapy to dornase alpha >or in patients intolerant of, or inadequately responseive to dornase alpha

Question 32

Agents improving CFTR protein function Ivacaftor (Kalydeco)

Answer 32

- First CFTR potentiator improving lung function - Potentiators: Increase cAMP-regulated aCl- ion channel open probability >increases Cl- secretion >reduces fluid absorption into airway epithelial cells >Increasing hydration of Airway Surface liquid >Resulting in increased ciliary beat frequency - Approved for gating mutation (Class III) G551D >in 2017 extended to include total of 33 mutations

Question 33

Agents improving CFTR protein function Ivacaftor/Lumicaftor (Orkambi)

Answer 33

Orkambi >indicated for CF PTs who are homozygous for F508del-CFTR >Combination approved in 2015 >This mutation present in approximately one-half of U.S. CF population Lumacaftor: Corrector >facilitates processing and trafficking of CFTR to cell surface >Improvement in lung function ppFEV1 (2.6 - 4 percentage points) >Reduction of pulmonary exacerbations (30-39% lower than placebo)

Question 34

Agents improving CFTR protein function Ivacaftor/Tezacaftor (Symdeco)

Answer 34

Symdeco >Indicated for CF PTs who are homozygous F508del-CFTR >Combination approved in 2018 Tezacaftor: Corrector >facilitates processing and trafficking of CFTR to cell surface >>Two copies of F508del-CFTR Or >>one F508del and one mutation that results in residual CFTR function

Question 35

Agents for pancreatic insufficiency

Answer 35

PI occurs in > 85% of CF PTs Enzyme preparation containing >Pancrelipase >>Amylase, Protease, Lipase >pH-sensitive, enteric-coated microspheres, microtablues or powders

Question 36

Supportive Therapy

Answer 36

Vitamin D >Osteoperosis treatment Physical therapy >lung drainage, stimulate coughing, clear airway phlegm Exercise Lung transplant >option for end stage pulmonary disease >11% of lung transplants in U.S. are from CF patients >40% of CF patients die while on waiting list >Five year survival rate is 60%

Question 37

Drugs in Pipeline

Answer 37

Drugs to: 1) Restore CFTR function (E.g. Ivacaftor, Orkambi, Symdeco) 2) Mucociliary Clearance (E.g. Dornase alpha, Hypertonic saline) >Inhaled mannitol (Bronchitol) only P3 3) Anti-inflammatory (E..g Ibuprofen) 4) Anti-infective (E.g. Amikacin Liposome Inhalation Suspension [Arikayce], Azithromycin) 5) Nutritional-GI-Other (E..g AquADEKs, Pancrelipase Enzyme Products)