Key Facts

Cystic fibrosis is a multisystem disease characterised by defective chloride and bicarbonate transport across epithelial surfaces. The introduction of CFTR modulator therapy has fundamentally transformed the disease trajectory, with dramatically improved lung function and life expectancy.

Epidemiology

Incidence is approximately 1 in 2,500 in the UK. Carrier frequency approximately 1 in 25 in Caucasian populations. Lower incidence in South Asian and Afro-Caribbean populations. Since the introduction of newborn screening in 2007, the majority of UK children are diagnosed in the neonatal period. Approximately 10,800 people live with CF in the UK.

Aetiology

Autosomal recessive inheritance. Over 2,000 mutations in the CFTR gene (chromosome 7q31.2) have been identified. Mutations are classified by functional effect:

• Class I: No protein production (G542X) — severe
• Class II: Protein misfolding/trafficking defect (F508del) — severe; most common
• Class III: Gating defect (G551D) — severe
• Class IV: Conductance defect (R117H) — milder
• Class V: Reduced quantity of normal protein — milder
• Class VI: Reduced surface stability — severe

Pathophysiology

Defective CFTR (a chloride/bicarbonate channel) on epithelial surfaces → impaired chloride secretion and excessive sodium/water absorption → thick, dehydrated secretions in lungs, pancreas, liver, intestines, and reproductive tract.

Lungs: Thick mucus impairs mucociliary clearance → chronic bacterial infection → neutrophilic inflammation → bronchiectasis → progressive lung destruction. Pseudomonas aeruginosa, Staphylococcus aureus, and Haemophilus influenzae are the key pathogens.

Pancreas: Thick secretions block pancreatic ducts → exocrine pancreatic insufficiency (85-90%) → fat malabsorption, steatorrhoea → progressive endocrine insufficiency (CF-related diabetes).

Liver: Biliary obstruction → focal biliary cirrhosis → multilobular cirrhosis in ~5-10%.

Reproductive: >95% of males are infertile (congenital bilateral absence of vas deferens, CBAVD). Females have reduced fertility due to thick cervical mucus.

Neonatal

• Meconium ileus (~15-20%): Failure to pass meconium, abdominal distension, vomiting
• Positive newborn bloodspot screening (elevated IRT)

Respiratory

• Chronic productive cough (initially Staph aureus, later Pseudomonas)
• Recurrent chest infections/pneumonia
• Progressive bronchiectasis
• Nasal polyps (~10-30%)
• ABPA (allergic bronchopulmonary aspergillosis)
• Haemoptysis (in advanced disease)
• Pneumothorax

Gastrointestinal

• Steatorrhoea (pale, offensive, bulky stools)
• Failure to thrive, poor weight gain
• Rectal prolapse
• DIOS (distal intestinal obstruction syndrome)
• CF-related liver disease

Endocrine

• CF-related diabetes (~20% by age 20, ~50% by age 30)
• Delayed puberty
• Osteoporosis (fat-soluble vitamin malabsorption)

Red Flags

• Massive haemoptysis (>250ml) — interventional radiology/bronchial artery embolisation
• Pneumothorax — chest drain; may recur
• Declining FEV1 below 30% predicted — consider lung transplant referral
• New-onset Pseudomonas — attempt eradication (NICE NG78)

Bedside

• Sweat test (pilocarpine iontophoresis): Gold standard — Cl⁻ >60 mmol/L = diagnostic; 30-59 = borderline; <30 = normal. Must collect ≥75mg sweat (100mg ideal)
• Growth: Plot height, weight, BMI — use CF-specific charts
• Pulse oximetry: Baseline SpO2
• Sputum culture: Regular MC&S for respiratory pathogens (Pseudomonas, Staph aureus, Burkholderia cepacia complex)

Bloods

• CFTR genotyping: Identify mutations — essential for CFTR modulator eligibility
• Fat-soluble vitamins (A, D, E, K): Commonly deficient
• LFTs: Screen for CF liver disease
• HbA1c / OGTT: Screen for CF-related diabetes annually from age 10 (OGTT preferred — HbA1c may underestimate)
• FBC: Baseline; may show iron deficiency
• Immunoglobulins, Aspergillus IgE/IgG: ABPA screening

Imaging

• CXR: Hyperinflation, bronchiectasis, mucus plugging
• CT thorax: Gold standard for bronchiectasis quantification
• Abdominal USS: Liver assessment, pancreatic changes

Special Tests

• Spirometry (from age ~5): FEV1 is the key outcome measure; progressive decline indicates disease progression
• Lung clearance index (LCI): More sensitive than FEV1 for early lung disease
• Faecal elastase: <200 μg/g = pancreatic insufficiency; <15 = severe

Non-pharmacological

• Airway clearance: Twice-daily physiotherapy — active cycle of breathing technique, autogenic drainage, oscillatory PEP (Acapella, Flutter), exercise
• Exercise: Strongly encouraged — improves lung function, quality of life, and survival
• Nutrition: High-calorie, high-fat diet (120-150% of normal caloric requirements); dietetic review at every clinic visit
• Cross-infection prevention: Strict segregation of patients with different organisms; individual clinic appointments

Pharmacological

• CFTR modulators (transformative therapy):
  • Elexacaftor/tezacaftor/ivacaftor (Kaftrio): For patients ≥6 years with at least one F508del mutation — NICE TA929; improves FEV1 by ~14%, reduces exacerbations by ~60%, improves BMI and QoL
  • Ivacaftor (Kalydeco): For G551D and other gating mutations — NICE TA398
• Pancreatic enzyme replacement (Creon): Lipase 500-2500 units/kg/meal; adjust to stool output
• Fat-soluble vitamins: A, D, E, K supplementation (e.g., CF-specific multivitamin)
• Mucolytics: DNase (dornase alfa 2.5mg nebulised OD) — cleaves DNA in sputum, improves FEV1; hypertonic saline (7%) nebulised BD
• Antibiotics:
  • Chronic Staph aureus: Flucloxacillin 12.5-25mg/kg QDS prophylaxis (from diagnosis in many centres)
  • Pseudomonas eradication: Nebulised tobramycin + oral ciprofloxacin at first isolation
  • Chronic Pseudomonas: Alternating monthly nebulised antibiotics (tobramycin, colistin)
  • Acute exacerbation: IV anti-pseudomonal antibiotics (e.g., ceftazidime 50mg/kg TDS + tobramycin 10mg/kg OD for 14 days)
• Azithromycin 250-500mg three times weekly: Anti-inflammatory effect; improves lung function in chronic Pseudomonas
• Ursodeoxycholic acid 10-15mg/kg BD: For CF liver disease
• Insulin: For CF-related diabetes

Surgical/Interventional

• Lung transplantation: Considered when FEV1 <30% predicted or rapid decline; median post-transplant survival ~9 years
• Liver transplantation: For end-stage CF liver disease
• Totally implantable venous access device (TIVAD/port): For recurrent IV antibiotics
• Gastrostomy: Supplementary feeding if unable to maintain adequate nutrition orally

Referral Criteria

• All children with positive NBS or sweat test — specialist CF centre
• Managed by specialist CF MDT: Respiratory physician, CF nurse specialist, physiotherapist, dietitian, psychologist, pharmacist, social worker
• NICE NG78: All CF care should be delivered by specialist centres

• Median predicted survival: >50 years for children born with CF today in the UK
• CFTR modulators: Expected to increase survival significantly further — early data suggests near-normal life expectancy may be achievable
• FEV1: Key prognostic indicator — FEV1 <30% predicted associated with 2-year mortality of ~30-40% (pre-modulator era)
• Pseudomonas colonisation: Associated with faster FEV1 decline — early eradication improves outcomes
• CF-related diabetes: Accelerates lung function decline; tight control improves outcomes
• Burkholderia cepacia complex: Associated with rapid decline and poor transplant outcomes; strict cross-infection measures essential
• Quality of life: Significantly improved with modulator therapy; treatment burden remains high

CFTR Mutation Classes and Modulators

CF Monitoring Schedule