Background Information

Definitions

Cystic fibrosis: genetic condition caused by CFTR gene mutations, leading to defective chloride transport, thick secretions, and multisystem involvement, most notably chronic lung disease and pancreatic insufficiency.^[Ref]

Epidemiology

UK Prevalence: ~ 1:2,500 live births ^[Ref]

Typical age of onset: infancy (identified through screening)

Aetiology

Genetics

• Affected gene → CFTR gene on chromosome 7 ^[Ref]
  • Encodes chloride and bicarbonate ion channels on epithelial cells
  • Most common mutation → F508del
• Inheritance pattern → Autosomal recessive

Pathophysiology

Sweat glands ^[Ref]

• Normal: CFTR reabsorbs Cl^– (and Na+ / H₂O indirectly) from sweat
• CF: Defective Cl^– reabsorption → excessive NaCl in sweat → ↑ sweat chloride concentration (diagnostic hallmark)

Other exocrine glands ^[Ref]

• Normal: CFTR secretes Cl^– (and Na+ / H₂O indirectly) into the gland lumen/ducts
• CF: defective secretion of electrolytes + water → thick, viscous secretions
  • Respiratory tract 
    • Mucus plugging → airway obstruction, chronic infection, neutrophilic inflammation
    • Progressive damage → bronchiectasis → respiratory failure (main cause of death)
  • Pancreas
    • Blocked ducts → autodigestion / fatty replacement of pancreatic tissue
    • Exocrine pancreas affected → Exocrine insufficiency
    • Endocrine pancreas affected → CF-related diabetes
  • Liver & biliary tree
    • Thick bile → focal obstruction & fibrosis → Liver disease (mild steatosis → cirrhosis)
  • GI tract 
    • Viscous secretions → meconium ileus in neonates; distal intestinal obstruction in older patients
  • Reproductive system
    • Males → viscous mucous obstructs vas deferens development (congenital absence of vas deferens) → obstructive azoospermia → infertility
    • Females → thick cervical mucous → may cause subfertility

Clinical features / Manifestations

General

Typical onset of disease manifestations

• Infancy → respiratory / gastrointestinal symptoms
• Childhood onwards → distal intestinal obstruction syndrome, cystic fibrosis-related diabetes, advanced hepatobiliary disease

Respiratory system

1. Obstructive lung disease characterised by progressive bronchiectasis (develops in all affected patients)

• Symptoms
  • Chronic cough + sputum production
  • Dyspnoea
  • Recurrent respiratory infections
  • Wheezing
• Signs / Examination findings 
  • Digital clubbing (in advanced disease)
  • On Auscultation → Crackles, wheezing

2. Chronic rhinosinusitis (30-70% affected) ^[Ref]

• Chronic nasal discharge / obstruction, facial pain, anosmia, nasal polyps

Gastrointestinal system

1. Bowel obstruction

• Meconium ileus (neonates)
  • Suspect if failure to pass meconium / bilious vomiting / abdominal distention in newborns
• Distal intestinal obstruction syndrome (DIOS; ~15-20% adults affected)

2. Constipation (may progress to DIOS or rectal prolapse)

3. Failure to thrive / poor growth (due to malabsorption)

Pancreas

1. Exocrine pancreatic insufficiency (~85% affected)

• Features: steatorrhoea (fatty stools), malabsorption & diarrhoea, abdominal distention

2. Endocrine pancreatic insufficiency

• Cystic fibrosis-related diabetes (~20% of adolescents / 40-50% of adults affected)

3. Pancreatitis (rare)

Cystic fibrosis-related liver disease

Cystic fibrosis-related liver disease is a less common manifestation that may manifest as: ^[Ref]

• Liver
  • Hepatic steatosis
  • Advanced liver disease (cirrhosis and portal hypertension)

 

• Biliary tract
  • Biliary fibrosis / strictures / cholangitis
  • Cholelithiasis

Prognosis

Median life expectancy: ~53 y/o in high-income countries ^[Ref]

Leading cause of morbidity / mortality → respiratory disease

Complications

Body system	Complications
Respiratory	Sinusitis and nasal polyps Chronic lung infections Bronchiectasis
GI	Meconium ileus (in newborn), distal intestinal obstruction syndrome (in adults) Fat-soluble vitamin deficiency (A D E K) Chronic liver disease Underweight / malnutrition
Metabolic	Diabetes (secondary) (affects up to 50% adults) Osteoporosis
Reproductive	Male infertility (obstructive azoospermia) – almost all males with CF are infertile Female subfertility
Genitourinary	Urinary stress incontinence

 

Guidelines

Screening

CF is routinely screened in newborns with the spot (heel-prick) test at ~5 days old

The screening marker is immunoreactive trypsinogen (IRT)

• Abnormal screening test → elevated IRT
  • This is NOT diagnostic → requires confirmatory sweat chloride testing as outlined below

Investigation and Diagnosis

If CF is suspected:

• Children and young people → sweat test (a small electrical current is used to drive pilocarpine into the skin to stimulate sweat glands, the sweat is then collected to measure the chloride concentration)
  • ↑ Sweat chloride concentration is seen in CF (since CFTR channels are defective, chloride cannot be reabsorbed from the sweat)
  • ≥60 mmol/L is a common diagnostic threshold

 

• Adults → CF genetic test

Management

CF is a multi-system condition, therefore the management can be split accordingly.

Respiratory

Long Term Management

Offer to all patients:

• Individualised exercise programme
• Airway clearance techniques
  • Recommended to be performed at least daily regardless of age or disease severity
  • If unable to use standard airway clearance techniques → consider non-invasive ventilation

 

• Mucoactive agent
  • 1st line: rhDNase (dornase alfa) (recombinant human deoxyribonuclease)
  • 2nd line: hypertonic sodium chloride +/- rhDNase
  • 3rd line: inhaled mannitol dry powder

CFTR modulators are not routinely offered to all patients, but only those with F508 deletion mutation in the CFTR gene. Examples:

• Lumacaftor-ivacaftor
• Tezacaftor–ivacaftor
• Ivacaftor–tezacaftor–elexacaftor

Note this is a simplification of the exact NICE technology appraisal guidance.

Infection Management

Antibiotic prophylaxis:

• Flucloxacillin in children up to 3 y/o, consider up to 6 y/o
• Long-term azithromycin if there is deteriorating lung function or repeated pulmonary exacerbation
  • As azithromycin has additional immunomodulatory and anti-inflammatory properties that reduce airway inflammation beyond its antibiotic effects

Choice of antibiotics for common infective organisms in CF:

Organism	Choice of antibiotic
Pseudomonas aeruginosa	Tobramycin Clistimethate sodium Ciprofloxacin
Staphylococcus aureus	Flucloxacillin
MRSA	Vancomycin Linezolid
Haemophilus influenzae	Co-amoxiclav Azithromycin

Monitoring and Assessment

Perform the following at each review:

• Oxygen saturation
• Chest X-ray
• Blood tests, including white cell count, aspergillus serology and serum IgE
• Respiratory samples (ideally sputum, or else cough swab or nasal pharyngeal aspirate) for microbiology investigations
• Spirometry including FEV1, FVC, FEF

Consider low-dose chest CT for children who have not had one before (can help detect early bronchiectasis).

Metabolic

Nutritional Interventions and Exocrine Pancreatic Insufficiency

• Increase calorie intake by eating high-energy food and increasing portion size (if there is weight loss and inadequate weight gain)
• Oral nutritional supplements (esp. fat-soluble vitamins)

Use stool elastase estimation to test for exocrine pancreatic insufficiency

• Offer oral pancreatic enzyme replacement therapy to those with exocrine pancreatic insufficiency
• Consider acid suppression agent (PPI or H2 receptor antagonist) if there is persistent malabsorption despite optimal pancreatic enzyme replacement therapy

CF-related Diabetes

Test for CF-related diabetes yearly from 10 y/o onwards with

• Continuous glucose monitoring, or
• Serial glucose testing over a few days, or
• OGTT

GI

Liver Disease

Perform yearly LFTs, if abnormal:

• Liver ultrasound scan, and
• Consider ursodeoxycholic acid

Distal Intestinal Obstruction Syndrome

Typical presentation:

• Vomiting and abdominal distension
• Palpable mass in right lower quadrant (from faecal loading)

Investigate with abdominal ultrasound or abdominal CT

Management:

• Ensure adequate hydration with oral or IV fluids
• 1st line: Gastrografin (diatrizoate meglumine and diatrizoate sodium solution) orally or via enteral tube
• 2nd line: macrogols ( iso-osmotic polyethene glycol and electrolyte solution) orally or via enteral tube
• Last resort: surgery

To reduce risk of recurrence:

• Encourage drinking plenty of fluids
• Optimise pancreatic enzyme replacement therapy
• Consider regular stool-softening agent (e.g. lactulose)

References