CF, Bronchiectasis, and OSA

Question 1

Cystic Fibrosis

Epidemiology

Answer 1

• Most common AR genetic disease of Caucasians
  
  • Northern European heritage most affected
  • Other populations less frequent
• ~ 30,000 cases in US ⇒ 1 per 2k-3k live births
• Survival ↑↑↑ in last 30 years
  
  • Median 39+ y/o

Question 2

CFTR

Gene

Answer 2

“Cystic fibrosis transmembrane regulator”

• Codes for a chloride channel
• Found at apical cell surface of secretory organs

Question 3

CFTR

Mutation

Answer 3

• AR genetic disease
• 1,500+ mutations identified so far
  
  • Only 5 mutations found in > 1%
• Most common mutation ⇒ ∆F508

Question 4

Cystic Fibrosis

Pathogenesis

Answer 4

Abnormal CFTR gene ⇒ absent, non-functioning, or hypo-functioning chloride channel.

Results in abnormal mucus which affects a variety of organs:

• Lungs ⇒ recurrent respiratory infections
• Pancreas ⇒ exocrine pancreatic insufficiency (85%)
  
  • Fat malabsorption
• Sweat glands ⇒ abnormally high sweat chloride
• Vas deferens ⇒ obstructive azospermia and male sterility
• Sinuses ⇒ recurrent sinus infections

Question 5

CF

Diagnosis

Answer 5

• Newborn screening ⇒ all 50 states
  
  • Heelstick for trypsinogen
    
    • Marker of pancreatic injury
    • Sensitive but not specific
• Sweat test ⇒ gold standard for diagnosis
  
  • Sweat chloride > 60 mmol/L
• Genotype testing ⇒ for two most prevalent CF mutations

Question 6

CF

Signs and Symptoms

Answer 6

• Pulmonary infection
• Pancreatic insufficiency
• ↑ Sweat Cl^- levels

Question 7

CF

Lung Disease

Answer 7

• Causes 95% of mortality and most of the morbidity in CF
• Abnormal airway secretions become infected with bacteria shortly after birth
  
  • Abx ↓ pathogen load
  • Infection can never be completely eradicated
  • Bacterial pathogens may change over time

Chronic respiratory infection or colonization ⇒ intermittent acute exacerbations ⇒ progressive decline in lung function ⇒ obstructive airways disease ⇒ ultimately respiratory failure

Question 8

CF

Major Pathogens

Answer 8

• Pseudomonas aeruginosa ⇒ present in 85% of pts by adulthood
• Staph. aureus
• Hemophilus influenza
• Other gram negative organisms

Question 9

CF

Treatment

Answer 9

Maintain aggressive airway clearance and a good pulmonary toilet.

• Chest physiotherapy
• Inhaled bronchodilators ⇒ SABA, LAMA, ICS
• Mucolytics ⇒ recombinant human DNAse
• Hypertonic saline 3%
• ± Suppressive antibiotics
  
  • Oral ⇒ Azithromycin 3x/week
  • Inhaled ⇒ nebulized tobramycin
• Nutritional support ⇒ pancreatic enzymes
• Aggressive weight management
• ± CFTR modulators

Question 10

CFTR Modulators

Answer 10

New class of drugs that act to improve function of defective CFTR protein.

• Act directly on CFTR channel itself
• Major revolution in CF treatment
• Extremely expensive
• Need to monitor for side effects

Question 11

Ivacaftor

Answer 11

• CFTR modulator drug
• At least one copy of G551D mutation
• Improved FEV₁ by 10% compared to placebo
• Follow LFT’s and eye exam (cataract risk)

Question 12

Lumacaftor-Ivacaftor

Answer 12

• CFTR modulator drug
• Homozygous for ∆F508 mutation
• Improved FEV₁ by 3%
• Reduced exacerbations by 30-40%
• Monitor LFT’s and eye exam
• Side effects
  
  • Chest pain
  • Menstrual irregularities

Question 13

CF

Acute Pulmonary Exacerbations

Answer 13

Defined as acute SOB, ∆ FEV₁, ∆ sputum

Treatment

• Continue normal therapy
• Add abx against primary pathogens
  
  • Mild exacerbation ⇒ can use PO
  • Severe exacerbation ⇒ need IV
  • Usually Pseudomonas aeruginosa
    
    • Requires high-dose, double coverage

Question 14

Advanced CF

Management

Answer 14

• Supplemental oxygen
• Non-invasive ventilation
• Lung transplantation ⇒ needs to be bilateral

Question 15

Bronchiectasis

Definition

Answer 15

Chronic necrotizing infection of the bronchi and bronchioles leading to abnormal dilation.

• Dilation must be permanent
• Can be seen after abnormal healing of infection
• Can be part of CF or Kartegener’s syndrome

Question 16

Bronchiectasis

Clinical Signs

Answer 16

• Severe, persistent cough
• Expectoration of copious amounts of foul-smelling, purulent sputum
• Fevers if pathogens present
• Symptoms start in childhood
• Later see hypoxia, hypercapnia, cor pulmonale

Question 17

Bronchiectasis

Pathophysiology

Answer 17

• Early changes reversible
• Changes irreversible if
  
  • Obstruction persists
  • Infection occurs, especially during growth
    
    • Airways develop abnormally
• Infection ⇒ inflammation of bronchial wall ⇒ bronchial damage ⇒ weakening and further dilation
• Lower lobes affected bilaterally
• Most severe in distal bronchi
• Airways become dilated up to 4x normal
• Severe form associated with CF

Question 18

Bronchiectasis

Histopathology

Answer 18

• Intense inflammatory exudate in bronchioles
• Desquamation and/or necrotizing ulceration of epithelium
• ± Squamous metaplasia of remaining epithelium
• Destruction of bronchial walls ⇒ ± lung abscess

Question 19

Obstructive Sleep Apnea (OSA)

Definition

Answer 19

• Repeated upper airway obstructions during sleep
• Partial or complete blockages
• Respiratory effort persists against a closed/partially closed upper airway

Question 20

OSA

Epidemiology

Answer 20

• 50% ♂ and 25% ♀ snore
• 3-7% of general population w/ OSA
  
  • Incidence underestimated
• Increases with age > 65
• Increased prevalence in:
  
  • African Americans
  • Asians
  • Men

Question 21

OSA

Risk Factors

Answer 21

• Obesity
• Male sex
• Neck circumference > 17 in
• Craniofacial abnormalities
• Active smokers
• Nasal congestion/obstruction
• DM
• Post-menopausal women

Question 22

OSA

Pathophysiology

Answer 22

• Anatomical obstruction
  
  • Nasal congestion
  • Reduced airway size
  • Physical obstruction
  • Positional effects
• Neuromechanical impairment
  
  • Decreased airway tone
  • Inappropriate timing of upper airway muscles during inspiration

Question 23

OSA

Clinical Signs & Symptoms

Answer 23

• Snoring
• Excessive daytime sleepiness
• Witnessed apneas
• Morning headaches
• Non-restorative sleep
• Depression
• Nocturia
• HTN, CAD, CVA

Question 24

OSA

Diagnosis

Answer 24

• Diagnosis can only be made by overnight sleep study
• STOP-BANG questionaire ⇒ for screening
  
  • Snoring, tired, observed, pressure, BMI, age, neck size, gender

Question 25

OSA Hypnogram

Answer 25

"Sleep study" * _Definitions_ * **Apnea** ⇒ cessation of airflow for 10 secs * **Hypopnea** ⇒ 30% airflow, 4% desaturation * **Central** ⇒ no effort or flow for 10 seconds * **Apnea-Hypopnea Index (AHI)** * Mild ⇒ 5-15 * Moderate ⇒ 15-30 * Severe ⇒ \> 30 events per hour

Question 26

OSA Treatment

Answer 26

* **Continuous Positive Airway Pressure (CPAP) ⇒** gold standard * Pneumatic airway splint * Weight loss of 10-20% * Positional therapy * Raise the head of bed * Tee shirt (ball) * Uvulopalatopharyngoplasty (UPPP) * Nasal steroids * Oral applicances * Mandibular advancement surgery * Tracheostomy

Question 27

CPAP Benefits

Answer 27

* 95% effective * Immediate solution * Non-invasive * Covered by insurance * Many mask types available * Machines are small and quieter now