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Cystic Fibrosis (CF)

NICE guideline [NG78] Cystic fibrosis: diagnosis and management. Published: Oct 2017.

Background Information

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

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

Typical age of onset: infancy (identified through screening)

  • 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 

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 

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

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 

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)

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 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 

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

Leading cause of morbidity / mortality → respiratory disease 

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

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

If CF is suspected:
  • Children and young people → sweat chloride test 
    • ↑ Sweat chloride level is indicative of CF
      • ≥60 mmol/L is a common diagnostic threshold
 
  • Adults → CF gene test

 

Although not explicitly stated in NICE guidelines, the sweat chloride test is regarded as the gold-standard diagnostic test for CF. Elevated sweat chloride reflects the underlying CFTR protein defect, whereas genetic testing may miss rarer CF mutations. 

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

Offer to all patients:
  • Individualised exercise programme
  • Airway clearance techniques
    • 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.

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
 

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 FEV1Forced expiratory volume in 1 second, FVCForced vital capacity, FEFForced expiratory flow

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

  • 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 (PPIProton pump inhibitor or H2 receptor antagonist) if there is persistent malabsorption despite optimal pancreatic enzyme replacement therapy

Test for CF-related diabetes yearly from 10 y/o onwards with
  • Continuous glucose monitoring, or
  • Serial glucose testing over a few days, or
  • OGTTOral glucose tolerance testing

Perform yearly LFTs, if abnormal:
  • Liver ultrasound scan, and
  • Consider ursodeoxycholic acid

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

Author: Noah T
Reviewer:
Last edited: 30/07/25