The CFTR Gene

Location: Long arm of Chromosome 7 (7q31.2). Function: Encodes a Chloride channel regulated by cAMP.

The 6 Classes of Mutations

Not all CF is the same.

Note: F508del accounts for >70% of alleles worldwide.

Genotype-Phenotype Correlation

• Pancreatic Status: Highly correlated with genotype. Class I-III are usually Pancreatic Insufficient (PI). Class IV-V are often Pancreatic Sufficient (PS).
• Lung Function: Less predictable. Environmental factors (smoke, infection) play a huge role.

The Maths of Inheritance

Autosomal Recessive Rules.

• Carrier + Carrier:
  • 25% Affected (CF).
  • 50% Carrier (Healthy).
  • 25% Non-Carrier (Healthy).
• Risk: If a sibling has CF, the healthy sibling has a 2/3 chance of being a carrier.

The Cascade of Failure

1. The Defect: CFTR channel fails to pump Chloride (Cl-) out of the cell into the airway lumen.
2. The Consequence: Because Cl- stays in, Sodium (Na+) is hyper-absorbed back into the cell (via ENaC channel) to balance charge.
3. The Water: Water follows Sodium (osmosis). It leaves the airway lumen.
4. The Result: The "Airway Surface Liquid" (ASL) layer dries out.
5. Mucociliary Failure: The cilia are crushed by thick, dehydrated mucus. They cannot beat.
6. Infection: Bacteria (Staph, Pseudomonas) are trapped and colonize the static mucus.
7. Destruction: Chronic Neutrophilic Inflammation -> Elastase release -> Bronchiectasis.

Respiratory

• Cough: Chronic, wet, purulent.
• Infection: Recurrent exacerbations.
• Bronchiectasis: Permanent dilation of airways (Signet ring sign on CT).
• Haemoptysis: Bronchial arteries bleed.

The Nose (Upper Airway)

The forgotten airway.

• Polyps: Benign swellings. Cause obstruction/loss of smell.
• Treatment: Steroid drops (Betnesol) or Surgery (FESS). Use of modulators often shrinks them!
• Sinusitis: Chronic reservoir for Pseudomonas.

Digital Clubbing

The Schamroth Sign.

• Mechanism: Platelet derived growth factor (PDGF) clumping in the fingers due to right-to-left shunting?
• Significance: Universal in advanced CF. If a "CF" child doesn't have clubbing, question the diagnosis (or they are very mild/screened early).
• Hypertrophic Osteoarthropathy (HPOA): Painful periostitis of wrists/ankles (associated with clubbing).

Gastrointestinal

• Meconium Ileus: 15% of newborns. Sticky meconium blocks terminal ileum.
• Pancreatic Insufficiency (85%): Blocked ducts causing autodigestion of pancreas -> Fibrosis -> No enzymes.
• Steatorrhoea: Large, pale, greasy, foul-smelling stools (fat malabsorption).
• CFRD: CF Related Diabetes (Insulin deficiency due to fibrosis + Insulin resistance).
• DIOS: Distal Intestinal Obstruction Syndrome (The adult equivalent of meconium ileus).
  • Mechanism: Sticky poop blocks the ileocaecal valve.
  • Trigger: Dehydration, Missed Creon.
  • Treatment: Hydration + Gastrografin (Oral contrast that draws water into gut). Surgery is a last resort.

Reproductive

• Men: 98% have Congenital Bilateral Absence of Vas Deferens (CBAVD). Infertility (Azoospermia). Sexual function is normal.
• Women: Viscid cervical mucus may reduce fertility, but most can conceive naturally.

Other Systems

• Sweat: Salty sweat (Risk of Hyponatremic Dehydration in heatwaves).
• Liver: Focal Biliary Cirrhosis (CFLD).
  • Pathology: Bile is thick -> plugs bile ducts -> cirrhosis -> Portal Hypertension.
  • Management: Ursodeoxycholic Acid (Urso). Monitor LFTs.
• Bones: Osteopenia/Osteoporosis.
  • Cause: Vit D deficiency + Inflammation + Steroids.
  • Tx: Bisphosphonates if severe.

The Revolution

Treating the cause, not just symptoms.

Kaftrio Impact

• FEV1: Increases by ~14%.
• Exacerbations: Reduced by 60-70%.
• BMI: Massive weight gain (patients need diet advice!).
• Sweat Chloride: Drops to near normal levels.

Modulator Side Effects

• Liver: Transaminase elevation (Check LFTs every 3 months).
• Eyes: Cataracts in children (Check eyes annually).
• Mental Health: Anxiety/Depression reported (Brain fog).

The Cost of Survival

Economics vs Ethics.

• Price Tag: Kaftrio costs ~$100k-$200k per patient per year.
• Access: Available in UK/USA/Europe. Developing world patients have no access ("The Genetic Lottery").
• Generic: Activists fight for generic production (Vertex patent challenge).

The Future: Gene Therapy

For the 10% who can't take Modulators.

• Method: Inhaled Viral Vectors or Lipid Nanoparticles to deliver correct mRNA/DNA.
• Challenge: Getting through the thick mucus to the epithelial cells.
• Status: Clinical Trials ongoing (Spirovant, Translate Bio).

Airway Clearance (Physiotherapy)

The daily grind. 20-30 mins, twice a day. Forever.

• Infants: Percussion / Tipping? (Old school). Now mostly bouncy bouncing.
• Children/Adults:
  • PEP Mask (Positive Expiratory Pressure): Splints airways open.
  • Flutter / Acapella: Oscillating PEP (shakes the mucus loose).
  • Autogenic Drainage: Breathing control technique.
  • The Vest: High frequency chest wall oscillation (Common in USA).

Lung Function Grading (FEV1)

• Normal: >80% predicted.
• Mild: 60-80%.
• Moderate: 40-60%.
• Severe: <40% (Transplant assessment begins).

The "Active Cycle of Breathing" (ACBT)

The most common technique.

1. Breathing Control: Relaxed tummy breathing.
2. Thoracic Expansion: Deep breath in + Hold 3 secs (gets air behind mucus).
3. Huffing: Forced Expiration Technique (Move mucus up).
4. Cough: Clear it out.

Exercise as Physio

• Benefit: Improves muscle strength, expands chest, mobilises mucus.
• Rule: "If you do 30 mins of vigorous sport (sweating/breathless), you can skip one physio session." (Varies by centre!).

Mucolytics

Thinning the glue.

1. DNase (Dornase Alfa): Enzyme that digests the DNA released by dead neutrophils (which makes mucus sticky). Inhaled daily.
2. Hypertonic Saline (7%): Draws water back into the airway (Osmosis) to rehydrate the ASL. Must give Salbutamol first to prevent bronchospasm.

Antibiotics

• Prophylaxis: Flucloxacillin (UK) to prevent Staph until age 3. Azithromycin (3x weekly) for anti-inflammatory effect.
• Exacerbations: 2 weeks of IV antibiotics (often home IVs via Port-a-cath).
• Nebulized: Tobramycin / Colomycin for chronic Pseudomonas suppression.

Nebulizer Hygiene

Avoiding self-infection.

• Risk: Nebulizer pots are wet, warm breeding grounds for Pseudomonas or Serratia.
• Protocol: Wash after every use. Steam sterilize (microwave bags) or boil daily. Replace pots every 3 months.

Totally Implantable Venous Access Devices (TIVAD)

The Port-a-Cath.

• Indication: Difficult venous access + Frequent IV courses (>3-4 per year).
• Placement: Subcutaneous reservoir on chest wall, catheter into SVC.
• Maintenance: Monthly flush (Heparin).
• Risk: Infection (Line Sepsis).

Creon (Enzyme Replacement)

Without this, food goes straight through.

• Dose: Titrated to fat content of meal.
• Rule: Taken with every meal/snack containing fat.
• Exceptions: Fruit, Juice, Jelly sweets, Cordial (No fat = No Creon).
• Signs of Under-dosing: Abdominal pain, bloating, floating stools.
• Signs of Over-dosing: Fibrosing Colonopathy (Rare strictures).

Diet

• High Calorie: 120-150% of RDA. "Fat is your friend".
  • Supplements: High energy drinks (Scandishake/Fortisip).
  • Tube Feeding: Overnight Gastrostomy (PEG) feeding is common if weight gain is poor.
• Salt: Extra salt supplements needed in hot weather/sport.
• Vitamins: Fat soluble (ADEK) supplements daily (Dalavit/Abidec).

Salt Supplementation

The forgotten nutrient.

• Loss: CF sweat has high salt concentration. In hot weather or sport, they lose massive amounts.
• Risk: Hyponatremic Dehydration (Pseudo-Bartter's syndrome).
• Dose: Sodium Chloride tablets or liquid added to milk for babies.

Pseudomonas aeruginosa

The enemy.

• Impact: Once established ("Mucoid"), lung function decline accelerates.
• Eradication Protocol: If new growth -> Oral Ciprofloxacin + Nebulized Colomycin for 3 months. Aim to clear it before it becomes mucoid.
  • Failure: If it becomes chronic, the patient needs long-term suppression (Nebs forever).
  • Cross-Infection: Never mix patients with different strains.

The Sputum Sample

The most important test.

• Protocol: Every clinic visit (even if well).
• Technique: Cough swab for babies, Sputum pot for older kids.
• Why?: To catch Pseudomonas early (before it becomes mucoid).

Drug Toxicity

The price of antibiotics.

• Aminoglycosides (Gentamicin/Tobramycin): Ototoxic (Deafness) and Nephrotoxic (Kidney failure).
• Monitoring: Trough levels must be checked religiously.
• Hearing: Annual Audiometry is mandatory.

Vaccination Schedule

• Flu Vaccine: Annual (Essential).
• Pneumococcal: PCV13 + PPSV23.
• Varicella: Check immunity (Chickenpox can be severe).
• COVID-19: Prioritized group.

Burkholderia cepacia complex

The disaster.

• Transplant: Often an absolute contraindication to lung transplant due to risk of fatal post-op sepsis ("Cepacia Syndrome").
• Segregation: Strict isolation in clinics. CF patients never meet other CF patients face-to-face.

Non-Tuberculous Mycobacteria (NTM)

• M. abscessus: Very hard to treat. Requires 18 months of triple antibiotics.

The Liver

• CFLD: Bile is thick -> plugs bile ducts -> cirrhosis.
• Ursodeoxycholic Acid: Used to improve bile flow.

CF Related Diabetes (CFRD)

Not Type 1, Not Type 2.

• Pathology: Fibrosis destroys Islet cells (Insulin deficiency) + Infection causes Insulin Resistance.
• Screening: Annual OGTT (Oral Glucose Tolerance Test) from age 10. (HbA1c is unreliable in CF due to RBC turnover).
• Treatment: Insulin. Oral hypoglycemics (Metformin) don't work well.
• Diet: Do NOT restrict calories. Give Insulin to match the high-calorie diet.

The Bones

• Bone Density: DEXA scans every 1-2 years from adolescence.

• Risk: Steroid use + Malabsorption + Inflammation.

• Action: Chest drain. Pleurodesis needed if recurrent.

COVID-19 and Shielding

The Surprise Result.

• Fear: Early pandemic prediction was that CF patients would die in huge numbers.
• Reality: Outcomes were surprisingly good (similar to non-CF).
• Shielding: 2 years of isolation caused significant deconditioning and mental health decline, even if it prevented COVID.

Haemoptysis

• Minor: Streaks. Treat infection.
• Major: >240ml. bronchial artery embolisation required. STOP NSAIDs and Physio.

Lung Transplantation

The last resort.

• Criteria: FEV1 <30%, Rapid decline, Massive haemoptysis.
• Contraindications: Burkholderia cenocepacia, NTM (sometimes), Poor adherence, BMI <18 or >35.
• Outcome: Median survival ~5-8 years post-transplant.
• Trade-off: Swapping one disease (CF) for another (Immunosuppression/Rejection).

End of Life Care

The difficult conversation.

• Advanced Directives: Should be discussed before acute failure.
• NIV as Ceiling: Often used for symptom relief (breathlessness) at end of life, not just for rescue.
• Palliative Team: Involve early for symptom control (Opioids for dyspnea).

The Transfer

• Moving from Pediatric (Family-centered) to Adult (Patient-centered) care.
• Timing: Process starts at 14, transfer at 16-18.
• Topics:
  • Fertility: Discuss CBAVD with boys.
  • Genetics: Carrier testing for partners.

  The Psychological Burden

A 2-hour daily routine.

• The Grind: Physio x2, Nebs x2, Creon x4, Antibiotics, Vitamins, Modulators.
• Depression: High prevalence in adolescents.
• "Survivor Guilt": Losing friends to CF while you survive (especially post-transplant or on Kaftrio).

Travel with CF

The Logistics.

• Insurance: Very expensive. Declare everything.
• Flight O2: Hypoxia at altitude. If sea-level sats <95%, may need in-flight oxygen (Fit-to-fly test).
• Medications: Carry in hand luggage (avoid freezing in hold). Letter from consultant required.

Fertility Guide

Fertility Guide

The Conversation to have early.

• Males: CBAVD (Congenital Bilateral Absence of Vas Deferens). The sperm are made in the testes but cannot get out.
  • Solution: Sperm retrieval (MESA/TESA) + ICSI (IVF). Success rates are high.
  • Contraception: Still needed! (STIs and the 2% chance of potency).
• Females: Thick cervical mucus.
  • Pregnancy: High risk but managed. Need to stop some drugs (ACEi, certain antibiotics). Kaftrio safety in pregnancy is being studied (often continued).

Pregnancy Protocol (MDT Care)

• Risks: Increased metabolic demand, reduced lung volume (baby pushes up diaphragm), GDM (Gestational Diabetes), Pre-term labour.
• Outcome: Generally good if lung function >50% at start.
• Breastfeeding: Encouraged (but baby needs sodium check as breast milk is low salt).

The Psychological Burden

Social Impact

Living a normal life.

• School: Missed days for appointments/IVs. "Special consideration" for exams.
• Work: Most adults work full time. Disclosure to employer is optional but recommended for appointments.
• Sports: Highly encouraged! Natural airway clearance.

The "Annual Review" Checklist

The yearly MOT.

1. Lungs: CXR, Spirometry, Sputum culture.
2. Pancreas: OGTT (Diabetes screen), Faecal Elastase (if unsure).
3. Liver: USS Liver (Cirrhosis check).
4. Bones: DEXA Scan (Osteoporosis).
5. Ears: Audiometry (Antibiotic damage).
6. Nutriton: Dietician review (BMI check).
7. Social: Psychology, School/Work performance.

Patient Instructions: Taking Creon

1. Timing: Take with the first mouthful of food.
2. Swallowing: Do not chew beads (They will ulcerate the mouth).
3. Capsules: Can be opened and granules mixed with apple puree for babies.
4. Dose: Adjust until poops are normal (brown logs).

Patient Instructions: Using a Flutter

1. Technique: Exhale slowly through device.
2. Sensation: Feel the vibration in the chest wall.
3. Action: Cough afterwards to clear the loosened phlegm.