Cystic Fibrosis

exocrine

- Lungs, GI, Pancreas

Cystic fibrosis is a dysfunction primarily of the ____ glands.

White/Caucasian

CF is the most common autosomal recessive disease in _____.

7

CF is inherited as an autosomal recessive trait. The CFTR gene responsible for the disease is located on the long arm of chromosome ____.

encodes for cystic fibrosis transmembrane conductance regulator (CFTR) protein, which contains 1480 amino acids

What protein does the CF gene code for, and how many amino acids does it contain?

CFTR is a chloride channel that regulates movement of chloride and bicarbonate across epithelial cells, affecting mucus viscosity, sweat electrolyte content, and pancreatic enzyme secretion

What is the functional role of the CFTR protein?

Defective CFTR leads to abnormal chloride and water transport, causing thick, sticky mucus, impaired mucociliary clearance, chronic lung infections, and pancreatic insufficiency

What happens in cystic fibrosis when CFTR is dysfunctional?

Mutations in the CFTR gene, most commonly ΔF508, a deletion of phenylalanine at position 508

What type of genetic mutation is responsible for cystic fibrosis?

Lungs

Pancreas

GI tract

Sinuses

Reproductive tract.

Which organ systems are primarily affected by the obstructive plugging of glands in CF?

High sweat chloride concentrations due to inability to reabsorb chloride in sweat ducts.

What causes the characteristic "salty sweat" in cystic fibrosis?

Thick secretions and developmental abnormalities lead to congenital bilateral absence of the vas deferens

How does CFTR dysfunction contribute to male infertility?

The sweat chloride test

What diagnostic test is considered the gold standard for confirming cystic fibrosis?

Pilocarpine

- Pilocarpine iontophoresis uses a mild electric current to carry pilocarpine into the skin to locally stimulate sweat glands, then the sweat is collected on filter paper or gauze. After 30-60 min, the filter paper is weighed and eluted in distilled water.

What chemical agent is used in the sweat chloride test to stimulate sweat production?

≥ 60 mEq/L

What sweat chloride value is considered diagnostic for cystic fibrosis?

40-60 mEq/L

What range of sweat chloride results is considered borderline and requires repeat testing?

2

How many sweat chloride tests must be performed?

1. Positive sweat chloride (≥ 60 mEq/L)

2. One or more clinical features consistent with CF:

- Chronic obstructive airway disease

- Intestinal malabsorption

- Family history of CF

- Meconium ileus at birth

- Male infertility due to azoospermia

- Presence of S. aureus or mucoid P. aeruginosa

What two components are required to diagnose cystic fibrosis?

1. Positive sweat chloride

2. Malabsorption

3. Chronic pulmonary disease

Classic triad for diagnosis of CF

Steatorrhea

What symptom of malabsorption is commonly seen in CF?

Because dysfunctional CFTR ion channels prevent reabsorption of chloride (and secondarily sodium) in the sweat ducts.

Why is CF sweat saltier than normal?

Hyponatremia and hypochloremia, due to high salt loss in sweat

What electrolytes abnormalities may be likely in patients with CF?

inhibits secretion of digestive enzymes, leading to malabsorption of fats, proteins, and carbohydrates.

Both exocrine and endocrine functions of the pancreas are affected in CF. Because of the defect in chloride transport, pancreatic secretions accumulate leading to obstruction which inhibits the secretion of ____.

48 hours

Meconium ileus is the failure to pass meconium within the first ___ hours of life and occurs in approximately 10-15% of newborns.

1. Abdominal distention

2. Bilious vomiting

3. Rectal prolapse

4. Meconium ileus

What are common symptoms of intestinal obstruction in infants with CF?

A reduction in volume and flow of bile, leading to stasis and obstruction of the biliary tree

- may develop gallstones

- focal biliary cirrhosis if chronic obstruction

What causes hepatic complications in cystic fibrosis?

Focal biliary cirrhosis

What long-term hepatic complication can occur in CF if biliary obstruction becomes chronic?

98%

What percentage of males with cystic fibrosis are infertile?

Obstruction or congenital absence of the vas deferens (CBAVD)

What causes male infertility in CF?

Production of thick, tenacious cervical mucus that impairs sperm penetration

Why does infertility occur in females with cystic fibrosis?

70-80%

What percentage of females with cystic fibrosis experience infertility?

Pulmonary system

What organ system is responsible for the majority of morbidity and mortality in cystic fibrosis?

1. Airway plugging

2. Bacterial adherence

3. Chronic bacterial colonization

In cystic fibrosis, defective chloride secretion and increased sodium/water reabsorption produce dehydrated, thick mucus. What complications does this cause in the airways?

Neutrophils

What immune cells primarily mediate the inflammatory response in CF airways?

Neutrophils release substances which perpetuate the inflammatory response. When they die, they release DNA, which significantly increases the viscosity of mucous.

- Chronic inflammation leads to progressive destruction

How do neutrophils worsen mucus viscosity in CF?

1. Pseudomonas aeruginosa (mucoid strain)

2. Staphylococcus aureus

3. Haemophilus influenzae

What are the three major bacterial pathogens involved in CF pulmonary infections?

Development of hypoxemia that progresses to pulmonary hypertension and can ultimately lead to cor pulmonale.

What is a major cardiopulmonary consequence of the extensive lung tissue loss that occurs in advanced cystic fibrosis?

- Increased work of breathing

- Increased metabolic demand from the underlying CF defect.

Why do patients with cystic fibrosis require a higher-than-normal caloric intake?

When oral intake cannot meet the increased caloric requirements, especially during illness or poor growth

When might CF patients need supplemental overnight nutrition (NG tube feeds)?

Patients lose excessive sodium and chloride in sweat due to impaired reabsorption, increasing risk of electrolyte imbalance and dehydration.

Why is salt replacement necessary in CF?

Because pancreatic obstruction leads to exocrine pancreatic insufficiency, preventing normal digestion of nutrients.

Why do CF patients require pancreatic enzyme replacement?

2,000-4,000 units of lipase per meal

What is the recommended PERT dose for infants < 1 year?

4,000-12,000 units of lipase per meal

What is the recommended PERT dose for patients > 1 year?

Give half the meal dose

How should PERT be adjusted for snacks?

lipase

PERT dosing is based on the ____ dose

To ensure enzymes are present in the duodenum at the same time as food, allowing digestion of fats, proteins, and carbohydrates

Why must PERT be taken with meals?

- Improve weight gain

- Minimize steatorrhea

- Eliminate abdominal cramping and bloating

Goals of PERT

DEAK (fat soluble)

CF patients must be supplemented with which vitamins?

Chest percussion + postural drainage

What are the two main components of traditional chest physiotherapy (CPT) in CF?

It mobilizes secretions from small airways, where expiratory flow is too low for coughing alone

Why is chest percussion important in CF airway clearance?

aerosol therapy with sterile water or saline

___ therapy is given before chest percussion to liquefy secretions

Bronchodilators:

- Albuterol nebs: 0.5 ml in 3 mL NS

- Albuterol MDI: 1-2 inhalations QID (children <12); 1-2 inhalations Q4-6 hours (>12)

What therapy may be added to open airways and improve response to aerosolized medications?

TMP-SMX

Doxycycline (≥ 8 years old)

Amoxicillin/clavulanate

Which antibiotics may be used for S. aureus in CF?

To achieve synergy, reduce resistance, and overcome poor lung penetration

Why must Pseudomonas aeruginosa be treated with two agents in CF?

Antipseudomonal beta-lactam: Zosyn

Aminoglycoside: Tobramycin

Which two classes are commonly paired to treat Pseudomonas in CF?

Piperacillin/tazobactam (Zosyn) 300-400 mg/kg/day IV divided Q8h

+

Tobramycin 2.5 mg/kg/dose IV Q8h or 7.5 mg/kg/day

What is the first-line IV antibiotic combination for treating Pseudomonas aeruginosa pulmonary infections in cystic fibrosis?

28 days on therapy, followed by 28 days off

What is the typical inhaled tobramycin cycle used to prevent resistance?

Ciprofloxacin

- good penetration into bronchial secretions

What is the only oral antipseudomonal agent available for CF patients?

Because animal studies show irreversible cartilage toxicity in weight-bearing joints.

Why is ciprofloxacin not commonly used in younger children?

Albuterol (bronchodilator)

Hypertonic saline (hydrator therapy)

Dornase alfa (Pulmozyme)

Chest physiotherapy (vest/percussion/postural drainage)

Inhaled antibiotics

What is the correct sequence for administering airway-clearance therapies in cystic fibrosis?

1.5 to 2

Patients with CF often need _____ times the number of calories as patients without CF

before meals or 1.5-2 hours after eating

When is the best time to complete chest physical therapy?

Correctors improve the folding, processing, and trafficking of misfolded CFTR proteins, increasing the amount of functional CFTR delivered to the cell surface.

What is the mechanism of action of CFTR correctors?

Lumacaftor

Elexacaftor

Tezacaftor

List the CFTR correctors

Potentiators increase the opening probability (gating) of CFTR channels already present at the cell surface, enhancing chloride transport across the membrane.

What is the mechanism of action of CFTR potentiators?

Ivacaftor

Deutivacaftor

List the CFTR potentiators

Amplifiers increase the overall amount of CFTR protein made in the cell, providing more CFTR substrate for correctors and potentiators to act on.

What is the mechanism of action of CFTR amplifiers?

transaminases and cataracts

Even though adverse effects with the CFTR modulators are often mild, monitoring for the elevation of ____ and ____ is currently recommended

ALT, AST, and bilirubin

What laboratory values must be monitored in all patients starting CFTR modulators due to the risk of hepatotoxicity?

Prior to initiation, every 3 months during the first year, and annually thereafter.

How often should transaminases be assessed after starting a CFTR modulator?

CFTR modulators have been associated with cataract development in pediatric patients

Why are baseline and follow-up ophthalmologic examinations recommended for pediatric patients starting CFTR modulators?

Lumacaftor/Ivacaftor (Orkambi)

- Start at one-half dose for the first 1-2 weeks to reduce this risk

Which CFTR modulator combination is associated with chest discomfort and dyspnea, especially in patients with poor baseline lung function?

CYP3A4

CFTR modulators should be used cautiously with ____ inducers/inhibitors

Lumacaftor/Ivacaftor (Orkambi)

Which CFTR modulator combination has more drug interactions: lumacaftor/ivacaftor (Orkambi) or tezacaftor/ivacaftor (Symdeko)?

fat

- Examples: eggs, butter, peanut butter, cheese pizza, avocado, whole dairy products

CFTR modulators must be taken with a high-____ meal to increase absorption.

Patients ≥ 1 year who are homozygous for delta F508

Who is Lumacaftor/Ivacaftor (Orkambi) approved for?

Patients ≥ 6 years old who are homozygous F508del or have one F508del allele plus another tezacaftor/ivacaftor-responsive mutation.

Who is Tezacaftor/Ivacaftor (Symdeko) approved for?

Patients ≥ 2 years old with at least one F508del mutation (heterozygous or homozygous).

Who is Elexacaftor/Tezacaftor/Ivacaftor (Trikafta) approved for?

Patients ≥ 1 month old who have a CFTR gating mutation (G551D) or another CFTR mutation demonstrated to be ivacaftor-responsive

Who is Ivacaftor (Kalydeco) approved for?

Patients ≥ 6 years old with at least one F508del mutation or another responsive CFTR mutation.

Who is Vanzacaftor/Tezacaftor/Deutivacaftor (Alyftrek) approved for?

Once daily dosing

What is the main advantage of Vanzacaftor/Tezacaftor/Deutivacaftor (Alyftrek) compared with Elexacaftor/Tezacaftor/Ivacaftor (Trikafta)?

dornase alfa and hypertonic saline; bronchodilators

In addition to nonpharmacological measures to facilitate mucus clearance, pharmacologic therapies, including mucolytics such as _____ and hyperosmolar agents such as aerosolized _____, are also used to improve mucus clearance. In addition, ____ are utilized to support ACT by opening the airway to facilitate the removal of secretions, along with deeper deposition of other inhaled medications into the smaller airways.

Selectively hydrolyzes extracellular DNA in CF sputum, reducing mucus viscoelasticity

MOA of Dornase Alfa (Pulmozyme)

Used in conjunction with standard therapies for the management of CF to improve pulmonary function and reduce exacerbations in patients ≥6 years old with asymptomatic/mild disease to moderate to severe disease.

Indication for Dornase Alfa (Pulmozyme)

2.5 mg (one single-use ampule) inhaled once daily via a recommended nebulizer

- Some patients may benefit from twice-daily dosing

What is the recommended dose of Dornase Alfa (Pulmozyme)?

Voice alteration, pharyngitis, rash, laryngitis, chest pain, conjunctivitis, rhinitis, ≥10% decrease in FVC, fever, and dyspnea

Common AEs of Dornase Alfa (Pulmozyme)