Key Facts

Cystic fibrosis (CF) is the most common autosomal recessive disease in Caucasians, caused by mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene. It results in defective chloride and bicarbonate transport, leading to thick, viscid secretions affecting multiple organs.

Epidemiology

• Incidence: ~1 in 2,500 live births in the UK (~800 new diagnoses/year)
• Prevalence: ~10,800 people living with CF in the UK
• Carrier frequency: ~1 in 25
• Median predicted survival: >50 years (improving dramatically with CFTR modulators)
• Equal sex distribution

Aetiology

• Mutations in CFTR gene (chromosome 7q31)

• 2,000 known mutations; ΔF508 accounts for ~70% of UK alleles

• CFTR mutations classified I-VI based on mechanism of protein defect
• ΔF508 is a class II mutation (defective protein processing)

Pathophysiology

• CFTR is a chloride and bicarbonate channel on epithelial cell surfaces
• Defective CFTR → reduced chloride secretion and increased sodium/water absorption
• Thick, dehydrated mucus in airways, pancreatic ducts, bile ducts, intestine, and vas deferens
• Lungs: mucus plugging → impaired mucociliary clearance → chronic infection → inflammation → bronchiectasis → respiratory failure
• Pancreas: duct obstruction → acinar destruction → exocrine insufficiency (85%) → endocrine insufficiency (CF-related diabetes, CFRD ~30-50% of adults)
• Liver: biliary obstruction → focal biliary cirrhosis (5-10%)
• GI: meconium ileus (neonatal), distal intestinal obstruction syndrome (DIOS, adults)
• Reproductive: CBAVD → male infertility (~98%)

Neonatal/Infancy

• Meconium ileus (~15-20% of CF neonates)
• Failure to thrive, poor weight gain
• Recurrent chest infections
• Steatorrhoea, bulky pale stools
• Prolonged neonatal jaundice
• Rectal prolapse

Childhood/Adolescence

• Chronic productive cough with purulent sputum
• Recurrent respiratory infections
• Nasal polyps (~30%), chronic sinusitis
• Finger clubbing
• Malabsorption, fat-soluble vitamin deficiency (A, D, E, K)
• Growth faltering

Adult

• Progressive bronchiectasis with Pseudomonas colonisation
• CF-related diabetes (30-50%)
• CF-related liver disease (5-10%)
• Infertility (male ~98%, female reduced)
• Osteoporosis
• Mental health: anxiety, depression
• Respiratory failure (main cause of death)

Red Flags

• Acute severe pulmonary exacerbation (increased sputum, fever, FEV₁ decline)
• Massive haemoptysis (bronchial artery erosion)
• Pneumothorax
• New Burkholderia cepacia complex isolation (associated with rapid decline)
• DIOS (acute abdominal obstruction)
• CF-related diabetes (new hyperglycaemia)

Bedside

• Sweat test: gold standard screening; sweat chloride ≥60 mmol/L diagnostic; 30-59 borderline
• Pulse oximetry: baseline and nocturnal
• Sputum MC&S: regular (at least 3-monthly) for colonising organisms

Bloods

• CFTR genotyping: confirm mutation (ΔF508, G551D, etc.)
• FBC: leucocytosis during exacerbation
• CRP: infection monitoring
• LFTs: CF liver disease screening
• HbA1c/OGTT: annual CFRD screening from age 10
• Fat-soluble vitamins (A, D, E): deficiency common
• Bone profile + DEXA scan: osteoporosis screening
• IgE, Aspergillus serology: ABPA screening

Imaging

• CXR: hyperinflation, bronchiectasis, mucus plugging, upper lobe predominant
• HRCT: detailed bronchiectasis assessment, mucus plugging
• CT sinuses: chronic rhinosinusitis/nasal polyps

Special Tests

• Spirometry: obstructive pattern; FEV₁ is the key monitoring parameter
• Faecal elastase: <200 µg/g confirms pancreatic exocrine insufficiency
• Sputum NTM culture: screen for non-tuberculous mycobacteria
• Annual OGTT: CF-related diabetes screening
• Newborn screening: heel prick test (day 5) — immunoreactive trypsinogen (IRT) + CFTR mutation analysis

Non-pharmacological

• Specialist CF centre management (NICE NG78)
• Airway clearance: twice daily minimum; active cycle of breathing technique, oscillatory PEP devices, postural drainage
• Exercise: regular aerobic exercise improves lung function and QoL
• Nutrition: high-calorie, high-fat diet (aim 120-150% of normal calorie intake); dietitian involvement
• Annual review: comprehensive assessment at CF centre

Pharmacological

CFTR modulators (transformative therapies):

• Elexacaftor/tezacaftor/ivacaftor (Kaftrio): for ≥1 copy of ΔF508 (covers ~90% of UK CF patients); NICE TA886
  • Improves FEV₁ by ~14%, reduces exacerbations by ~63%, improves BMI and QoL
• Ivacaftor (Kalydeco): for G551D gating mutations; NICE TA398
• Lumacaftor/ivacaftor (Orkambi): for ΔF508 homozygotes (largely superseded by Kaftrio)

Respiratory:

• Nebulised DNase (dornase alfa) 2.5mg OD: thins mucus, improves FEV₁
• Nebulised hypertonic saline (6-7%) BD: aids mucus clearance
• Inhaled antibiotics: tobramycin nebulised 300mg BD (month on/off) or colistin 1-2 MU BD for chronic Pseudomonas
• Oral azithromycin 250-500mg 3×/week: anti-inflammatory

Exacerbations:

• IV anti-pseudomonal antibiotics: tobramycin + ceftazidime or meropenem (14 days)
• Guided by previous sputum sensitivities

Pancreatic/GI:

• Pancreatic enzyme replacement (CREON): dose adjusted to food intake (10,000-25,000 units lipase per meal)
• Fat-soluble vitamin supplementation (A, D, E, K)
• Ursodeoxycholic acid: for CF liver disease
• CFRD: insulin therapy (metformin not routinely used)

Surgical/Interventional

• Bilateral lung transplantation: for end-stage respiratory failure (FEV₁ <30% or rapid decline)
• Liver transplantation: for end-stage CF liver disease
• Bronchial artery embolisation: massive haemoptysis
• Surgery for pneumothorax: VATS pleurodesis (avoid extensive pleurectomy to preserve transplant option)
• Surgery for DIOS: conservative first; laparotomy if conservative fails

Referral Criteria

• All CF patients managed at specialist CF centre
• Transplant assessment when FEV₁ <30% or rapid decline despite optimal therapy
• Fertility: reproductive medicine referral for assisted conception

• Median predicted survival: >50 years (and rising with CFTR modulators)
• In 1960s, median survival was ~5 years
• FEV₁ is the strongest predictor of mortality
• Kaftrio has dramatically improved outcomes — expected to significantly extend life expectancy
• Burkholderia cepacia infection: associated with accelerated decline and sometimes excluded from transplant
• Post-lung transplant: median survival ~8-10 years
• CFRD: associated with worse pulmonary outcomes and reduced survival
• NTM infection (especially M. abscessus): challenging to treat; may affect transplant eligibility

CFTR Mutation Classes

CF Complications Summary