Cystic Fibrosis

Pathophysiology of CF

• Gene: CFTR gene mutation on heavy arm of Chromosome 7 (most common: $\Delta F508$).
• Defect: Abnormal/Absent CFTR protein function.
• Mechanism (Airway):
  1. Impaired $C{l}^{-}$ secretion into lumen.
  2. Hyperabsorption of $N{a}^{+}$ (via disinhibited ENaC)
  3. Water follows $N{a}^{+}$ paracellularly $\to$ Dehydrated Airway Surface Liquid (ASL).
  4. Ciliary dyskinesia + Viscous mucus $\to$ Bacterial colonization.

Clinical features

Respiratory:

• Upper: Nasal polyps, Pansinusitis.
• Lower: Bronchiectasis (upper lobe predominant), ABPA, Recurrent infections (Staph. aureus early, Pseudomonas late).

Gastrointestinal:

• Newborn: Meconium ileus, Peritonitis.
• Child: DIOS, Rectal prolapse, GERD.

Pancreatic/Hepatic:

• Exocrine insufficiency (Steatorrhea, FTT, ADEK deficiency).
• Endocrine: CFRD.
• Liver: Focal biliary cirrhosis $\to$ Portal hypertension.

Genitourinary:

• CBAVD (Congenital Bilateral Absence of Vas Deferens) in males ($95\%$).
• Delayed puberty/Amenorrhea in females.

Functional Classification of Mutations

A. Severe Mutations (No functional CFTR at membrane)

Usually associated with Pancreatic Insufficiency and classic CF phenotype.

• Class I: Defective Protein Synthesis (No Protein)

  • Mechanism: Nonsense, frameshift, or splice-site mutations lead to premature stop codons. No stable CFTR protein is created.
  • Example: G542X, W1282X.
  • Therapy: “Read-through” agents (under research).

• Class II: Defective Processing & Trafficking (No Traffic)

  • Mechanism: Protein is synthesized but misfolded in the Endoplasmic Reticulum (ER). It is recognized by the proteasome and degraded, failing to reach the cell surface.
  • Example: Phe508del (ΔF508) - Most common mutation worldwide.
  • Therapy: Correctors (e.g., Lumacaftor, Tezacaftor) help fold the protein and transport it to the surface.

• Class III: Defective Regulation/Gating (No Function)

  • Mechanism: Protein reaches the cell surface but the channel gate does not open in response to cAMP stimulation.
  • Example: G551D.
  • Therapy: Potentiators (e.g., Ivacaftor) force the channel gate open.

B. Mild Mutations (Residual CFTR function)

Often associated with Pancreatic Sufficiency and milder lung disease.

• Class IV: Defective Conductance (Less Function)

  • Mechanism: Protein reaches the surface and the gate opens, but the pore is narrowed, reducing the flow (conductance) of Chloride ions.
  • Example: R117H.
  • Therapy: Potentiators can help increase flow.

• Class V: Defective Splicing/Reduced Quantity (Less Protein)

  • Mechanism: Splicing defects or promoter mutations lead to a reduced amount of normal functional CFTR mRNA and protein.
  • Example: A455E.

• Class VI: Accelerated Turnover (Less Stability)

  • Mechanism: Functional protein reaches the surface but is unstable and rapidly internalized/degraded (reduced half-life).
  • Example: rPhe508del (rescued ΔF508 often exhibits this instability).

Summary Table

Class	Defect	Protein Status	Severity	Example	Therapy
I	Synthesis	Absent	Severe	G542X	None
II	Trafficking	Misfolded	Severe	ΔF508	Correctors
III	Gating	Closed	Severe	G551D	Potentiators
IV	Conductance	Low Flow	Mild	R117H	Potentiators
V	Quantity	Low Amount	Mild	A455E	Potentiators
VI	Stability	High Turnover	Mild	-	Stabilizers

Diagnosis of Cystic Fibrosis

• Cystic fibrosis (consensus diagnostic criteria)
• Should match one clinical and one laboratory criteria
  • Clinical criteria
    • Clinical suspicion of CF – recurrent pneumonia, Meconium ileus in the first 24 hours, failure to thrive, steatorrhea, nasal polyps
    • Newborn screening test positive (positive immunoreactive trypsinogen test)
    • Family history of cystic fibrosis
  • Laboratory criteria
    • 2 different CF mutations
    • One abnormal nasal potential difference
    • 2 positive sweat chloride test in two different occasions
  • Sweat chloride test
    • Sweat is  induced by pilocarpine induced inotophorosis (Gibson cooke method)
    • Minimum sweat of 75 mg is analysed
      • If < 29 mmol/lit – normal
      • 29-59 mmol/lit – intermediate

      • 60 mmol/lit – diagnostic

  • Genetic analysis
    • 2 CF mutation present – diagnostic
    • If <2 mutation present – clinical suspicion / equivocal
  • Nasal potential difference
    • Used in intermediate / equivocal sweat chloride test or <2 CF mutation present
    • More negative basal potential difference and large drop with amiloride is characteristic

Management of Cystic Fibrosis

Pulmonary measures

1. General Measures

• Nutrition (High calorie/protein), Hydration, Vaccination (Flu, Pneumococcal).

**2. Airway Clearance Therapy (ACT) - The “Toilet of Lung” **

• Sequence is vital:
  1. Bronchodilators: (Salbutamol) to prevent bronchospasm.
  2. Mucolytics:
     • Hypertonic Saline (3-7%): Hydrates airway surface liquid.
     • Dornase Alfa (Recombinant human DNase): Cleaves extracellular DNA from neutrophils, decreasing viscosity.
  3. Chest Physiotherapy: ACBT, PEP mask, Flutter device, or HFCWO (Vest).

3. Antimicrobial Therapy

• Prophylaxis/Eradication: Early eradication of P. aeruginosa (Inhaled Tobramycin + Oral Ciprofloxacin).
• Chronic Suppression: Inhaled Tobramycin (TOBI) or Aztreonam (cycles of 28 days on/off).
• Acute Exacerbations:
  • Two antipseudomonal IV antibiotics (e.g., Ceftazidime + Amikacin) for 14 days.
  • Pharmacokinetics: Larger volume of distribution requires higher doses.

4. Anti-Inflammatory Therapy

• Azithromycin: Oral, 3 days/week. Reduces exacerbations & improves FEV1 (immunomodulatory effect).
• Ibuprofen: High dose (rarely used due to toxicity monitoring).
• Note: Systemic steroids only for ABPA/Asthma.

5. CFTR Modulators (Genotype specific)

• Potentiators (Class III/IV): Ivacaftor. Keeps the gate open (e.g., G551D)
• Correctors (Class II): Lumicaftor / Tezacaftor. Helps folding/trafficking (e.g., F508del).
• Triple Therapy: Elexacaftor + Tezacaftor + Ivacaftor (Current Gold Standard for F508del).

6. Advanced Management

• Management of complications: Pneumothorax, Hemoptysis (Bronchial artery embolization).
• Lung Transplantation (End-stage).

Non pulmonary management

Non-Pulmonary Complication Management in CF

1. Gastrointestinal & Nutritional Management

• Pancreatic Insufficiency (PI):
  • PERT: Pancreatic Enzyme Replacement Therapy (e.g., Creon) with all meals and snacks. Dosing based on fat intake (500-2500 units lipase/kg/meal).
  • Vitamins: Supplementation of fat-soluble vitamins (A, D, E, K) in water-soluble formulations.
• Nutrition:
  • High-calorie, high-fat diet aiming for 110–200% of RDA for age.
  • Overnight enteral feeding (gastrostomy) if failure to thrive persists.
• Salt Supplementation: * Oral NaCl supplements required due to sweat losses, especially in infants and hot climates.

2. Intestinal Complications

• Distal Intestinal Obstruction Syndrome (DIOS):
  • Prevention: Adequate hydration, adjusting enzyme dose, laxatives (PEG).
  • Treatment: Rehydration + Oral/Nasogastric Polyethylene Glycol (PEG) or Gastrografin enemas. Surgery rarely needed.
• GERD: Proton Pump Inhibitors (PPIs) improve enzyme efficacy.

3. Hepato-biliary (CFLD)

• Cholestasis/Liver Disease: Ursodeoxycholic acid (UDCA) (20 mg/kg/day) to delay progression.
• Monitoring for portal hypertension (varices management).

4. Metabolic (CFRD)

• CF Related Diabetes: * Insulin is the treatment of choice.
  • Oral hypoglycemic agents are ineffective.
  • Do not restrict caloric intake.

5. Reproductive

• Infertility (CBAVD in males): Sperm retrieval (MESA/TESA) + ICSI.
• Genetic Counseling: Essential for family planning.

Novel therapy

1. Mechanism

• Definition: Small molecule therapies that target specific defects in the CFTR protein rather than treating downstream symptoms (Precision Medicine).
• Prerequisite: Requires CFTR Genotyping prior to initiation.
• Mechanism of Action Classifications:
  1. Potentiators: Increase the “open probability” of the CFTR channel (keep the gate open).
     • Target: Gating mutations (Class III), e.g., G551D.
     • Drug: Ivacaftor.
  2. Correctors: Assist in the folding and trafficking of the protein to the cell surface.
     • Target: Folding mutations (Class II), e.g., F508del.
     • Drugs: Lumacaftor, Tezacaftor, Elexacaftor.

2. FDA-Approved Regimens & Indications

Current therapy often combines correctors and potentiators for synergistic effect.

Brand Name	Composition	Indications / Genotype	Age Approval (varies)
Kalydeco	Ivacaftor (Monotherapy)	Gating mutations (e.g., G551D), R117H	> 4 months
Orkambi	Lumacaftor + Ivacaftor	Homozygous F508del	> 2 years
Symdeko	Tezacaftor + Ivacaftor	Homozygous F508del OR residual function mutation	> 6 years
Trikafta	Elexacaftor + Tezacaftor + Ivacaftor	At least one F508del mutation (Heterozygous or Homozygous)	> 2 years

• Note on Trikafta: Considered a major breakthrough as it covers ~90% of the CF population.

3. Other Novel Non-Modulator Agents

• Inhaled Mannitol: Osmotic agent to improve mucociliary clearance.
• Inhaled Aztreonam: Suppression of P. aeruginosa.
• Anti-inflammatory: High-dose Ibuprofen (monitoring required), potential future role of Acebilustat (LTA4 hydrolase inhibitor).

4. Adverse Effects & Monitoring

• Hepatotoxicity: Transaminitis common. Monitor LFTs baseline, q3mo (1st year), then annually.
• Respiratory: Chest tightness/bronchospasm (specifically with Lumacaftor).
• Ophthalmological: Non-congenital cataracts reported in pediatric patients. Baseline and follow-up slit lamp exam recommended.
• Drug Interactions: Metabolized by CYP3A. Dose adjustment needed with azoles (itraconazole/voriconazole) and macrolides (clarithromycin).