Cystic Fibrosis

What is cystic fibrosis?

A genetic condition caused by a mutation in the gene that encodes for the cystic fibrosis transmembrane conductance regulator (CFTR) protein

• Autosomal recessive inheritance pattern

• Most often affects those of Caucasian descent

What is the pathophysiology of CF?

• Impaired transport of chloride across epithelial cell and into lumen

• dehydration of luminal fluid

• impaired flow of luminal fluid and/or risk of luminal obstruction

• organ damage

Describe the CFTR protein

• Found on secretory epithelial cells

• functions as an ion channel, moving chloride ions outside the cells

What are some organ systems that are affected by CF?

• sweat glands

• pancreas

• liver

• respiratory system

• GI system

• reproductive tract

What test is the gold standard?

Sweat test

A sweat test that is >60 mmol/L means?

Diagnostic for CF

What are some diagnostics of CF?

• Newborn screening (NBS)

  • heelstick

• CFTR variant panel

  • blood test for common CFTR mutants/variants

• sweat test

Historically, the cornerstone of CF management has been _______ management in conjunction with the prevention and treatment of lung infections

symptomatic

Pulmonary manifestations of CF are due to what processes?

• Impaired transport of Cl- across the pulmonary epithelium

• Dehydration of airway lumen surface liquid (mucus)

• Ineffective mucociliary clearance due to increased viscosity of mucus

  • Mucus obstruction, inflammation, and infection

• Pulmonary scarring (fibrosis), which leads to increased lung compliance

Pulmonary management strategies include _______ for inflammation and _______ for infections

azithromycin; inhaled ABX

How do we help mucus obstruction?

Airway clearance therapy

What are some therapies for airway clearance?

1. albuterol

2. hypertonic saline

3. dornase alfa

Hypertonic saline is used in kids >_____ yo and dornase alfa is used is kids >_____ yo

6; 5

Azithromycin is prescribed to patients with CF as a ______-times weekly regimen

3

Azithromycin dose for 18-36kg is _______ and if >36kg is _____

250mg; 500mg

The use of azithromycin is recommended in what groups?

1. Patients who are 6+ yo with chronic P. aeruginosa infection

2. Patients who are 6+ yo NOT chronically infected with P. aeruginosa

What is the purpose of azithromycin with CF?

• prevents formation of chronic P. aeruginosa biofilm formation

• anti-inflammatory activity

Mechanism of why azithromycin has anti-inflammatory activity

Inhibits neutrophil migration and decreases production of pro-inflammatory mediators

Purpose of inhaled antibiotics as part of maintenance regimen?

Eradicate or suppress the growth of bacterial organisms of concern

*mainly P. aeruginosa

Regimen of inhaled ABX for eradication vs suppression?

Eradication: 28-day tx course X 1

Suppression: Cycled 28- day treatment course followed by a 28-day off-treatment period, continued

What are the 2 main FDA approved inhaled ABX used in CF?

1. Tobramycin

2. Aztreonam

True or false: tobramycin and aztreonam are used for BOTH eradication and suppressive therapy

false; tobramycin is both but aztreonam is mainly suppressive

Tobramycin is used in children >____yo and aztreonam is used in children >____yo

6; 7

When do you de-escalate airway therapies?

• Stable on CFTR modulator

• stable or improved FEV1

• minimal respiratory symptoms

• no recent pulmonary exacerbations

How do we de-escalate airway therpaies?

• Reduce or discontinue ONE therapy at a time

• Continue monitoring FEV1 and respiratory symptoms

• Reassess before making other changes

Define acute pulmonary exacerbations

Acute worsening of respiratory symptoms (cough, sputum production/quality change, SOB, and decline in FEV1)

What is our therapeutic goal in acute pulmonary exacerbations?

return to baseline FEV1

How do we manage acute exacerbations?

1. Temporarily increase maintenance airway therapies

   1. Increase albuterol and AWC to 4x/day

   2. Increase Dornase to 2x/day

2. Initiate combo ABX therapy (systemic tx)

3. Treat with ABX for 10-14 days

What are some PK differences seen in CF?

• increased Vd

  • needing higher doses

• increased renal and non-renal clearance

  • more frequent dosing

What is the gold standard in covering Pseudomonas in CF?

Double anti-pseudomonal coverage

What is the rationale behind double anti-pseudomonal coverage?

1. Add a synergistic effect

2. Help avoid resistance

What is the role of pancreatic exocrine gland cells and alkaline pancreatic fluid?

• Exocrine gland cells: secrete digestive enzymes

• Alkaline pancreatic fluid:

  • solubilize the digestive enzymes

  • transport digestive enzymes to the duodenum

How does CF affect the functions of the pancreas?

• Chloride secretion is impaired

• thick, sticky mucus replaces the free-flowing pancreatic fluid that is normally produced

• altered secretions obstruct the pancreatic duct and prevents digestive enzymes from reaching the duodenum

What is the result of pancreatic insufficiency?

• weight loss

• malnourishment

• poor growth

True or false: normal growth is associated with improved lung function in children with CF

true

How do we diagnose pancreatic insufficiency?

• Annual fecal elastase screening

• Fecal elastase < 200 mcg/g

How do we manage pancreatic insuffciency?

• High-calorie, high-fat diet

• Supplementation of fat-soluble vitamins

• PERT

True or false: PERT therapy is NOT formulation-specific, and the brands are interchangeable

False

How do we dose PERT in infants and children?

Infants: Weight x 13,000 divided by the number of feeds/day

• Max 13,000 lipase units/kg/day

Children: 2,500 lipase units/kg/meal

• Max: 10,000 lipase units/kg/day

• Snacks = ½ mealtime dose

What is the goal 25-hydroxyvitamin D value?

>30ng/mL

What is the role of vitamin D supplementation in CF?

• should be supplemented as cholecalciferol based on patient-specific vitamin D level and age

• Reassess vitamin D levels 3 months after a change and annually once stable

How does CF influence diabetes?

Pancreatic duct obstruction leads to chronic inflammation and intrinsic damage to pancreatic cells, including beta cells

This leads to insulin insufficiency an insensitivity

How do we screen, manage, and monitor diabetes in CF?

1. Screen with oral GTT at 10 y/o

2. Manage with moderate aerobic exercise (150mins/week) and insulin therapy

3. Monitor BG checks 3x per day, quarterly A1c measurements, complications, lipid profile annually (if high risk)

What are the CFTR mutation classes?

• No (functional) protein

  • Faulty product

• Receptor trafficking issue

  • Right protein, wrong place

• Protein functionality issue

  • Dysfunctional gate or channel

• Protein quantity issue

  • Everything is right, but not enough protein is produced

What do potentiators do?

Increase the function of CFTR channels already on the cell surface

Which CFTR therapy is a potentiator ONLY?

Kalydeco

What are correctors?

“Correct” misfolded CFTR proteins and increase their processing and trafficking to the cell surface

What drugs are the correctors?

1. Orkambi (homozygous F580del)

2. Symdeko

Which drugs are triple therapy?

1. Trikafta

2. Alyftrek

Triple therapy leads to major increases in what?

FEV1

What makes Orkambi and Symdeko differ from one another?

• Symdeko has greater # of mutations, fewer DDIs, and lower ADE incidence

• Orkambi is approved for 1 yo rather than 6 yo with Symdeko

What is the differences between the 2 triple therapy options?

Trikafta: approved in 2+

Alyftrek: once daily dosing

BOTH have eligibility for rare mutation

Counseling points of CFTR modulators

• Doses should be taken with a high-fat snack or meal

• The packet formulations can be mixed with a tsp of soft food or 5 mL of liquid

  • food should be at or below room temperature

  • entire dose should be taken within 1 hour of mixing

ADR of CFTR modulators

• Cataracts

• Hepatotoxicity

• GI effects

• CNS effects

• Increased BP and ICP

• Acne/skin rash

• Arthralgia (Kalydeco)

• Respiratory symptoms (Orkambi)

Monitoring of CFTR modulators

• Annual ophthalmologic exam

• LFT at baseline, Q3 months x 1 year and then annually