Chapter 20 · Cystic Fibrosis (CF)

Epidemiology · Pathogenesis · Genetics · Microbiology · Diagnosis · Clinical features (pulmonary, GI, other) · Treatment (airway clearance, inhaled therapies, CFTR modulators, nutrition) · Monitoring progress · Management of advanced disease · The future
📌 Core principles: CF is the most common life-limiting autosomal recessive disorder in Caucasians (CFTR gene). Diagnosis: newborn screening (IRT/DNA), sweat chloride ≥60 mmol/L, CFTR mutation analysis. Multisystem: progressive lung disease (bronchiectasis, P. aeruginosa), pancreatic insufficiency (steatorrhoea, FTT), CF-related diabetes, liver disease. Treatment: airway clearance, inhaled dornase alfa/hypertonic saline, azithromycin, CFTR modulators (ivacaftor, lumacaftor/ivacaftor, elexacaftor/tezacaftor/ivacaftor), pancreatic enzyme replacement, fat-soluble vitamins. Advanced disease: lung transplantation, end-of-life care.

📖 Cystic Fibrosis – Key Concepts

🌍 Epidemiology & Genetics
Incidence 1:2500-3500 in Caucasians; autosomal recessive. CFTR gene (7q31.2); >2000 mutations; F508del most common (70%). Pathogenesis: defective CFTR protein → decreased chloride/bicarbonate secretion, increased sodium absorption → thick mucus, impaired mucociliary clearance, inflammation.
🦠 Microbiology
Early: S. aureus, H. influenzae. Later: P. aeruginosa (mucoid phenotype), B. cepacia complex, MRSA, NTM, A. fumigatus. Chronic infection drives bronchiectasis.
🩺 Diagnosis
Newborn bloodspot (IRT, DNA). Sweat test (≥60 mmol/L) gold standard. CFTR mutation analysis (two disease-causing mutations). Positive family history, clinical symptoms (meconium ileus, FTT, recurrent chest infections).
🫁 Clinical features (pulmonary)
Chronic cough, wheeze, recurrent pneumonia, bronchiectasis, digital clubbing, haemoptysis, pneumothorax, respiratory failure. CF-related asthma, allergic bronchopulmonary aspergillosis (ABPA).
🍽️ GI & other manifestations
Pancreatic insufficiency (85%) → steatorrhoea, FTT, fat-soluble vitamin deficiency. Meconium ileus (neonate). Distal intestinal obstruction syndrome (DIOS). CF-related liver disease (multilobular cirrhosis). CF-related diabetes (CFRD). Male infertility (CBAVD).
💊 Treatment overview
▪️ Airway clearance (chest physiotherapy, oscillating devices).
▪️ Inhaled therapies: dornase alfa (Pulmozyme), hypertonic saline (7%), tobramycin (alternating months), aztreonam.
▪️ Systemic antibiotics for exacerbations.
▪️ CFTR modulators: ivacaftor (potentiator), lumacaftor/ivacaftor, elexacaftor/tezacaftor/ivacaftor (ETI) – transformative for eligible genotypes.
▪️ Pancreatic enzyme replacement therapy (PERT).
▪️ High-calorie diet, fat-soluble vitamins (ADEK).
▪️ Management of CFRD, liver disease, osteoporosis.
▪️ Lung transplantation for advanced disease.
📈 Monitoring & advanced disease
Annual review: spirometry, sputum culture, BMI, OGTT, vitamin levels, bone density. Advanced disease: FEV1 <40% predicted, frequent exacerbations, oxygen dependency, noninvasive ventilation (NIV), lung transplant evaluation.

🔎 Symptom-based approach: CF diagnosis and complications

1️⃣
Newborn with intestinal obstruction, abdominal distension, bilious vomiting, no passage of meconium. – Meconium ileus (CF until proven otherwise). Contrast enema (may relieve) or surgery; confirm with sweat test/CFTR genetics.
2️⃣
Toddler with chronic cough, FTT, steatorrhoea, salty skin. – CF. Sweat test >60 mmol/L, CFTR analysis.
3️⃣
Child with CF, chronic P. aeruginosa, progressive FEV1 decline, frequent exacerbations. – Advanced lung disease. Inhaled tobramycin (alternating months), azithromycin, consider CFTR modulator if eligible; evaluate for lung transplant.
4️⃣
CF patient with acute abdominal pain, vomiting, palpable right lower quadrant mass, no bowel obstruction. – DIOS (distal intestinal obstruction syndrome). Treat with oral gastrografin, IV fluids, N-acetylcysteine enemas.
5️⃣
CF adolescent with polyuria, polydipsia, weight loss, random glucose 15 mmol/L. – CF-related diabetes (CFRD). Oral glucose tolerance test (OGTT). Insulin therapy required.
🚨 CF red flags: Massive haemoptysis (bronchial artery embolisation), sudden worsening dyspnoea (pneumothorax), liver cirrhosis with varices (portal hypertension), severe pulmonary exacerbation with respiratory failure (NIV, intubation, transplant evaluation).

📋 CF management algorithms (pulmonary, GI, modulator)

🫁
CF pulmonary maintenance (standard of care)
▪️ Daily airway clearance (chest physiotherapy, positive expiratory pressure, oscillating device).
▪️ Inhaled dornase alfa (Pulmozyme) – reduces sputum viscosity.
▪️ Inhaled hypertonic saline (7%) twice daily – improves mucociliary clearance.
▪️ Azithromycin (250-500 mg 3x/week) – anti-inflammatory reduces exacerbations.
▪️ Inhaled tobramycin (28 days on/off) for chronic P. aeruginosa.
▪️ CFTR modulator (elexacaftor/tezacaftor/ivacaftor) for eligible (F508del and others).
🍽️
Nutrition and pancreatic management
▪️ Pancreatic enzyme replacement therapy (PERT) with meals/snacks (lipase units per gram fat).
▪️ High-calorie, high-fat diet, tube feeds if poor weight gain.
▪️ Fat-soluble vitamin supplementation (ADEK).
▪️ Monitor for CF-related diabetes (annual OGTT from age 10).
💊
CFTR modulator by genotype (2024 guidelines)
▪️ F508del homozygous: elexacaftor/tezacaftor/ivacaftor (ETI).
▪️ F508del heterozygous + residual function mutation: ETI.
▪️ Gating mutations (G551D): ivacaftor monotherapy.
▪️ Minimal function mutations: ETI (for some). Modulators improve FEV1, reduce exacerbations, improve QoL.
🩸
Management of CF exacerbation (acute)
▪️ Increase airway clearance, inhaled bronchodilator.
▪️ Oral/IV antibiotics based on sputum culture (anti-pseudomonal if P. aeruginosa).
▪️ Systemic corticosteroids if ABPA.
▪️ IV antibiotics for 10-14 days (e.g., ceftazidime + tobramycin, or meropenem).

💡 Reflex prompts – Cystic Fibrosis

🧬 Most common CFTR mutation in Caucasian CF patients.
F508del (deletion of phenylalanine at position 508).
🩺 Gold standard diagnostic test for CF.
Sweat chloride test (≥60 mmol/L).
🦠 Most common pathogen in CF lung disease in adults.
Pseudomonas aeruginosa (mucoid phenotype).
💊 First-line CFTR modulator for F508del homozygous patients (age ≥2y).
Elexacaftor/tezacaftor/ivacaftor (Trikafta/Kaftrio).
🍽️ A child with CF, steatorrhoea, and FTT. Treatment?
Pancreatic enzyme replacement therapy (PERT) with meals, fat-soluble vitamins.
📉 A CF patient with FEV1 35% predicted, frequent exacerbations, oxygen dependency. Next step?
Evaluate for lung transplantation (bilateral sequential lung transplant).
🚨 A CF patient with sudden haemoptysis (250 mL). Immediate management?
Airway protection, bronchial artery embolisation (if massive, recurrent).
🍬 A CF adolescent with polyuria, weight loss, elevated HbA1c. Diagnosis?
CF-related diabetes (CFRD). Insulin therapy required.
🩸 A newborn with meconium ileus. Immediate next test?
Sweat test and CFTR gene sequencing.
🧪 Inhaled therapy used to reduce sputum viscosity in CF.
Dornase alfa (Pulmozyme) – DNase enzyme.