Cystic fibrosis

• Autosomal recessive disease caused by missions in CFTR that causes a syndrome of respiratory disease, pancreatic insufficiency, constipation, and other disorders arising from the increased thickness of mucous production

Background

Pathophysiology

• Caused by mutations in the CFTR gene which encodes the cystic fibrosis transmembrane conductance regulator, a cAMP-regulated chloride channel
• CFTR is present in epithelial cells lining the airways, biliary tree, intestines, vas deferens, sweat ducts, and pancreatic ducts >2000 possible defects, causing a wide range of presentations
• Most common is delta-F508 (which falls into classes II, III, and VI)
• Classified into:
  • Normal
  • I: no synthesis (e.g. a nonsense or frameshift mutation)
  • II: blocked processing or folding
  • III: blocked regulation or a gating problem
  • IV: altered conductance
  • V: reduced synthesis
  • VI: unstable and quickly degraded

Microbiology

• In childhood, Staphylococcus aureus and Haemophilus influenza are most common
• By young adulthood, Pseudomonas followed by Staphylococcus aureus are most common
• Others include Aspergillus, Stenotrophomonas maltophilia, Burkholderia cepacia, and MRSA
• Non-tuberculous mycobacteria are also involved, especially Mycobacterium abscessus and Mycobacterium avium complex

Epidemiology

• Autosomal recessive disease
• 1:3300 Caucasians
• 1:25 carriers

Clinical Manifestations

• On newborn screening, with increased serum trypsinogen (take top 2% and sequence for most common mutations)

Differential Diagnosis

• For positive sweat chloride test:
  • Untreated Addison disease
  • Ectodermal dysplasia
  • Some glycogen storage diseases
  • Untreated hypothyroidism
  • Adulthood

Investigations

• Sweat chloride concentration greater than 60 mEq/L (or 90 mEq/L for adults) with an appropriate clinical context or family history
• Genotyping

Diagnosis

• Must have both clinical features and positive diagnostic testing
• Clinical features include cystic fibrosis, family history, or positive newborn screen
• Diagnostic tests including 2x CF mutations, or 2x positive sweat chloride test

Management

Chronic Management

• Overall goals are to preserve lung function by decreasing infection, inflammation, and mucous production
• Chronic *Pseudomonas *infection defined as >50% of cultures positive for Pseudomonas in the past 12 months
• Vaccinations
• Decrease mucous burden with mucolytics (hypertonic saline or Pulmozyme)
  • Chronic productive cough or FEV1 < 90%, start mucolytic
  • Mild lung disease, no daily cough, and FEV1 >90%, physician and patient decision
  • When starting, needs a trial of mucolytics with before-and-after PFTs to ensure no bronchospasm
• Decrease bacterial burden with inhaled antibiotics (tobramycin, aztreonam)
  • Chronic growth of Pseudomonas, chronically suppress
  • New growth of Pseudomonas, attempt to eradicate with short course
  • B. cepacia complex, physician decision
  • Stenotrophomonas maltophilia, physician decision
  • Achromobacter xyloxidans, physician decision
• Decrease inflammation with chronic oral azithromycin
  • Chronic growth of Pseudomonas, treat if no Mycobacteria
  • B. cepacia complex, no guidelines
  • Staph aureus, H. influenzae, physician decision (small benefit)
  • Rule out non-tuberculous mycobacteria first
• Targeted therapies
  • For G551D (3% of cases) (a class III defect in gating), ivacaftor (VX700) is an experimental agent that causes an absolute increase in FEV1 by 10%

Acute Management

• See Cystic fibrosis pulmonary exacerbation
• See Cystic fibrosis antibiotic dosing

Prognosis

• FEV1 is main predictor of survival
• FEV1 starts declining after Pseudomonas colonization
• Survival decreases with increasing pulmonary exacerbations
  • 25% fail to recover to 90% of baseline FEV1
  • 40% fail to recover to 100% of baseline FEV1
• Life expectancy is 1 year once FEV1 drops to 20% of predicted