Cystic Fibrosis in Paediatrics
Definition
Cystic Fibrosis is a chronic, multisystem autosomal recessive disorder caused by mutations in the CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) gene.
It leads to defective chloride and bicarbonate transport across epithelial cells, resulting in thick, dehydrated secretions affecting mainly the lungs, pancreas, liver, intestines, and reproductive tract.
It is one of the most common life-limiting inherited diseases in children, particularly in populations of European ancestry but can occur worldwide.
Pathophysiology
The disease occurs due to mutation of the CFTR gene on chromosome 7.
Normal CFTR Function
CFTR protein acts as:
- Chloride channel in epithelial cells
- Regulates sodium and water transport
- Maintains thin mucus secretions
In Cystic Fibrosis
Mutation leads to:
- Defective chloride secretion
- Increased sodium absorption
- Water follows sodium → dehydrated mucus
- Thick viscous secretions
Organ Effects
- Lungs: mucus plugging → infection → bronchiectasis
- Pancreas: blocked ducts → pancreatic insufficiency
- Intestine: meconium ileus
- Liver: biliary cirrhosis
- Sweat glands: high chloride in sweat
Genetics
- Inheritance: Autosomal recessive
- Gene: CFTR gene (chromosome 7q31)
- Most common mutation: ΔF508 (F508del)
Types of CFTR Mutations
- Defective protein production
- Defective processing
- Defective regulation
- Reduced conduction
- Reduced protein synthesis
Causes / Risk Factors
Primary cause is genetic mutation.
Risk factors include:
- Family history
- Consanguinity
- Carrier parents
Carrier frequency varies by population.
Clinical Features
Symptoms usually begin in infancy or childhood.
Respiratory Manifestations
- Chronic cough
- Thick sputum
- Recurrent pneumonia
- Wheezing
- Bronchiectasis
- Nasal polyps
- Chronic sinusitis
- Digital clubbing
Common pathogens:
- Staphylococcus aureus
- Pseudomonas aeruginosa
- Burkholderia cepacia
Gastrointestinal Manifestations
- Meconium ileus in neonates
- Failure to thrive
- Malabsorption
- Steatorrhea
- Abdominal distension
- Rectal prolapse
Pancreatic Manifestations
- Pancreatic insufficiency
- Fat-soluble vitamin deficiency
- Pancreatitis
Hepatobiliary Manifestations
- Neonatal cholestasis
- Hepatomegaly
- Biliary cirrhosis
- Portal hypertension
Electrolyte Abnormalities
Children may develop:
Pseudo-Bartter syndrome
- Hyponatremia
- Hypochloremia
- Metabolic alkalosis
Reproductive Effects
- Male infertility due to congenital absence of vas deferens
- Reduced female fertility
Complications
Major complications include:
Respiratory
- Bronchiectasis
- Respiratory failure
- Pneumothorax
- Hemoptysis
Gastrointestinal
- Distal intestinal obstruction syndrome (DIOS)
- Pancreatitis
Metabolic
- CF-related diabetes mellitus
Hepatic
- Cirrhosis
Nutritional
- Severe malnutrition
Investigations / Diagnosis
1. Newborn Screening
- Immunoreactive trypsinogen (IRT)
2. Sweat Chloride Test (Gold Standard)
Pilocarpine iontophoresis used.
Interpretation:
- ≥60 mmol/L → Diagnostic
- 30–59 mmol/L → Intermediate
- <30 mmol/L → Normal
3. Genetic Testing
Detects CFTR mutation.
4. Other Investigations
Respiratory evaluation
- Chest X-ray
- HRCT chest
- Sputum culture
- Pulmonary function tests
Pancreatic evaluation
- Stool elastase
- Fecal fat test
Liver tests
- LFTs
- Ultrasound abdomen
Differential Diagnosis
Conditions with similar features include:
- Primary ciliary dyskinesia
- Severe asthma
- Bronchiectasis of other causes
- Immunodeficiency disorders
- Chronic aspiration
- Celiac disease (for malabsorption)
Management
Treatment is multidisciplinary and lifelong.
Goals:
- Improve lung function
- Prevent infections
- Maintain nutrition
- Manage complications
Non-Pharmacologic Management
Airway Clearance Therapy
Includes:
- Chest physiotherapy
- Postural drainage
- Positive expiratory pressure devices
- High-frequency chest wall oscillation
Nutritional Therapy
High-calorie diet
- 120–150% of normal caloric intake
- High fat diet
Vitamin supplementation
- Vitamins A, D, E, K
Salt supplementation especially in hot climates.
Pharmacologic Treatment
1. Dornase Alfa
Dornase alfa
Indication
- Reduce mucus viscosity in CF
Mechanism
Breaks down extracellular DNA in sputum, reducing mucus thickness.
Usual Dose
Children ≥5 years:
- 2.5 mg nebulized once daily
Pharmacokinetics
- Administered via inhalation
- Minimal systemic absorption
Adverse Effects
- Voice alteration
- Pharyngitis
- Rash
Contraindications
- Hypersensitivity
Monitoring
- Lung function
- Symptom improvement
Patient Counselling
- Use nebulizer correctly
- Continue physiotherapy
2. Hypertonic Saline (3–7%)
Indication
Improve airway clearance.
Mechanism
Draws water into airway mucus.
Dose
- 4 mL nebulized 2–4 times daily
Adverse Effects
- Bronchospasm
- Cough
Bronchodilator may be given before inhalation.
3. Antibiotics
Used for acute infections and chronic suppression.
Tobramycin
Tobramycin
Indication
Chronic Pseudomonas infection
Mechanism
Inhibits bacterial protein synthesis (30S ribosomal subunit).
Dose
Inhaled therapy:
- 300 mg nebulized twice daily in 28-day cycles
IV dose (severe infection):
- 10 mg/kg/day divided doses
Pharmacokinetics
- Poor oral absorption
- Renal elimination
Adverse Effects
- Nephrotoxicity
- Ototoxicity
- Bronchospasm (inhaled)
Contraindications
- Severe renal impairment (relative)
Drug Interactions
- Other nephrotoxic drugs
Monitoring
- Renal function
- Drug levels (IV)
4. Azithromycin
Azithromycin
Indication
Anti-inflammatory and infection control in CF.
Mechanism
Inhibits bacterial protein synthesis (50S ribosomal unit).
Dose
Children:
- 10 mg/kg three times per week
Pharmacokinetics
- Long half-life
- Hepatic metabolism
Adverse Effects
- GI upset
- QT prolongation
- Hearing loss (rare)
Monitoring
- ECG in long-term therapy
5. Pancreatic Enzyme Replacement
Pancrelipase
Indication
Pancreatic insufficiency.
Mechanism
Provides lipase, amylase, protease.
Dose
Children:
- 500–2500 units lipase/kg per meal
Adverse Effects
- Constipation
- Perianal irritation
Monitoring
- Weight gain
- Stool fat
6. CFTR Modulator Therapy
Examples:
- Ivacaftor
- Lumacaftor + Ivacaftor
- Tezacaftor + Ivacaftor
- Elexacaftor + Tezacaftor + Ivacaftor
Example:
Ivacaftor
Ivacaftor
Mechanism
Improves CFTR channel opening.
Dose
Depends on mutation and age.
Adverse Effects
- Elevated liver enzymes
- Cataracts in children
Monitoring
- Liver function tests
Surgical Management
In severe disease:
- Lung transplantation
- Liver transplantation (rare)
Prognosis
With modern therapy:
- Median survival now >40–50 years in developed countries.
- Early diagnosis and CFTR modulators significantly improve outcomes.
Major cause of death:
- Respiratory failure
Prevention
- Genetic counselling
- Carrier screening
- Prenatal diagnosis
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