cystic fibrosis (CF, mucoviscidosis)

Epidemiology

• Caucasians:
  • 1 in 2000-3500 live births
  • 1 in 20 (3-5%) are heterozygous carriers
  • the most common lethal genetic disease in Caucasians
• Blacks: 1 in 17,000 live births
• Asians: 1 in 90,000 live births
• no sex predominance
• 10% of cases diagnosed in patients > 10 years of age

Pathology

• clinical manifestations reflect alterations in exocrine secretions such that mucus becomes excessively thick & tenacious
• impaired mucociliary clearance
• bacterial colonization of airways
• lysis of neutrophils releases DNA & actin filaments further reducing mucociliary clearance
• the DNA in purulent sputum forms a viscous gel that that increases viscosity of sputum
• chronic inflammation leads to bronchiectasis, obstructive lung disease, pulmonary fibrosis & cor pumonale
• all exocrine glands, except sweat glands are adversely affected; sweat becomes salty
• 10% of patients & carriers develop hyper-responsive airways & asthma
• 10% of patients develop bronchopulmonary aspergillosis
• azoospermia is due to congenital absence of a vas deferens
  • congenital bilateral absence of the vas deferens may represent a mild form of cystic fibrosis
  • majority of men with cystic fibrosis lack the vas deferens

Genetics

• autosomal recessive, with asymptomatic heterozygous carriers
• mutations in the cystic fibrosis transmembrane regulator (CFTR) gene, which encodes an epithelial chloride channel
• about 70% of patients carry the same mutation, a deletion of phenylalanine 508 in one of the two CFTR ATP-binding domains (F508del)
  • this mutation results in a temperature-sensitive defect in protein processing (not in aberrant regulation by ATP)
  • at 27 C, the mutant form of CFTR forms functionally active chloride channels, but at 37 C, it gets stuck in the maturation pathway & fails to reach plasma membrane, thus giving rise to a very severe disease state in which epithelial chloride channels are absent
• about 400 different mutations are known
• other implicated genes
  • PLCZ1

Clinical manifestations

• pulmonary (97% of adult CF patients)
  • accounts for most of the morbidity & mortality
  • chronic & progressive with acute exacerbations
  • almost always begins in the upper lobes
  • hyperinflation, bronchiectasis & microabscesses occur secondary to mucous plugging
  • chest may be hyperresonant to percussion
  • chronic productive cough with purulent sputum
  • atelectasis
  • hemoptysis (60-71% of adult CF patients)
  • pneumothorax (16% of adult CF patients)
  • recurrent or persistent lower respiratory tract infections (pneumonia)
    • Pseudomonas aeruginosa (most common)
    • Haemophilus influenzae
    • Staphylococcus aureus
    • Burkholderia cepacia
    • nontuberculous mycobacterial infection
  • allergic bronchopulmonary aspergillosis
• extrapulmonary manifestations include:
  • upper respiratory tract (48% of adult CF patients)
    • chronic sinusitis
    • nasal polyps
  • intestinal:
    • constipation
    • volvulus
    • intussusception
    • fecal impactation
    • rectal prolapse
    • chronic diarrhea, steatorrhea
  • pancreatic:
    • malabsorption (95%), but seldom symptomatic
    • malnutrition
    • pancreatitis
    • diabetes mellitus
  • hepatobiliary:
    • fatty liver
    • cholelithiasis
    • biliary cirrhosis
    • portal hypertension
  • genitourinary
    • infertility & sterility: azoospermia (95% of males)
      • may rarely present in adulthood with isolated azoospermia as only symptom
    • epididymitis
  • skeletal
    • hypertrophic osteoarthropathy
    • retardation of growth
    • retardation of bone maturation
    • demineralization of bone
    • clubbing

Laboratory

• sweat chloride using pilocarpine iontophoresis is the gold standard for diagnosis of CF
  • > 80 meq/L is abnormal in adults; > 60 meq/L in children
  • abnormal results on at least 2 tests is necessary for diagnosis
  • a negative sweat chloride in an adult does not rule out CF
  • confirm bronchiectasis prior to sweat chloride (see Radiology:)
    • immunoglobulins in serum if bronchiectasis confirmed prior to sweat chloride
• respiratory/sputum culture & sensitivity using oropharyngeal swab
  • at least quarterly
  • common organisms include:
    • Pseudomonas aeruginosa
      • dominant organism
      • impossible to eradicate
    • Pseudomonas cepacia (Burkholderia cepacia)
      • associated with rapid deterioration in lung function
    • Staphylococcus aureus
    • Haemophilus influenza
• cystic fibrosis genotyping (PCR/southern blot)
• sperm analysis
  • azoospermia
  • absence of fructose from the seminal vesicles
• newborn screening may be of benefit
• screen for development of pancreatic insufficiency using fecal elastase
• see ARUP consult

Diagnostic procedures

Pulmonary function tests:

• obstructive pattern with evidence of air trapping & bronchial hyper-reactivity in some patients
• later in the course of the disease, hypoxemia & hypercapnia

Radiology

• chest X-ray
  • hyperinflation
  • bronchiectasis & hilar adenopathy
  • microabscesses
  • increased interstitial reticular marking
  • upper lobes are generally more involved than the lower lobes
• chest computed tomography
  • high-resolution computed tomography (CT) of thorax to confirm bronchiectasis
  • no more frequently than every 2-3 years
  • risk of radiation exposure may exceed benefit
• abdominal imaging: dilated loops of small intestine

Differential diagnosis

(in adults)

• features favoring cystic fibrosis
  • clinical features of cystic fibrosis
  • positive family history
  • sweat chloride > 80 meq/L
  • pancreatic insufficiency
• common variable immunodeficiency
  • complication of autoimmune disorder

Management

• goals of therapy:
  • control infections
    • exacerbations of pulmonary infections may present subacutely
    • treat any change in pulmonary function as infection
    • most patients are chronically infected with Pseudomonas aeruginosa
    • maintenance aerosolized tobramycin for control of chronic pulmonary infection
    • maintenance azithromycin may be useful
  • provide bronchopulmonary hygiene
• antibiotics:
  • 3rd generation cephalosporin + aminoglycoside (dual IV coverage)
  • empiric coverage for Pseudomonas aeruginosa
  • because of increased clearance & volume of distribution, larger than usual doses of antibiotics may be needed
  • inhaled antibiotics for new or chronic Pseudomonas aeruginosa infection
    • direct aerosolized tobramycin
    • suppression of chronic pulmonary infections
    • NOT useful for infectious exacerbations
• chest physiotherapy & postural drainage
  • daily airway clearance therapy
  • more frequently during exacerbations
• nutrition
  • adequate hydration
    • high-salt diet, especially in summer or warm locations
  • pancreatic enzyme replacement (pancrelipase) & fat soluble vitamin supplemention as indicated
• treat reactive airway disease (asthma)
  • evidence is insufficient to recommend for or against use of bronchodilators, ibuprofen, leukotriene modifiers, azithromycin
  • avoid systemic or inhaled glucocorticoids
• recombinant human deoxyribonuclease I (rhDNAse)
  • FDA-approved
  • decreases viscoelasticity of sputum
  • dornase alpha (Pulmozyme) 2.5 mg/day inhaled via jet nebulizer
    • adverse effects:
      • pharyngitis, laryngitis, rash, chest pain, conjunctivitis
  • rhDNAse therapy associated with decreased mortality
• CFTR potentiator therapy
  • oral ivacaftor 150 mg PO every 12 hours improves pulmonary function in patients with CFTR mutation G551D
  • ivacaftor/lumacaftor (Orkambi) FDA-approved for patients with 2 copies of the CFTR mutation F508del
  • ivacaftor/tezacaftor for patients homozygous for CFTR mutation Phe508del
  • one of two CFTR correctors VX-445 & VX-659 used in combination with ivacaftor/tezacaftor for patients homozygous for CFTR mutation Phe508del improved forced expiratory volume
  • elexacaftor added to tezacaftor + ivacaftor improves lung function & quality of life in cystic fibrosis with F508del
• aerosolized hypertonic saline (7%) may be useful
• mannitol dry powder may be useful for patients with FEV1 decline > 2% annually who cannot tolerate rhDNAse (see NGC {NICE})
• oxygen therapy
  • CPAP for nocturnal hypoxemia or hypercarbia
• organ transplantation
  • 10.3% of Canadians vs 6.5% of Americans may contribute to longer survival in Canadians
  • bilateral lung transplantation - 3 year survival is 50-55%
  • liver transplantation for advanced liver disease
• gene therapy
  • not yet successful
  • nebulised nonviral CFTR gene-liposome complex every 4 weeks for 1 year
• preventive medicine
  • pneumococcal vaccination PCV13 & PPSV23 8 weeks later
  • annual flu vaccine
  • patients with cystic fibrosis should wear masks during ambulatory care visits except in the exam room
  • patients should not wait with other patients in reception area
  • clinicians should follow Contact Precautions
• prognosis:
  • mean age of survival significantly increased from 2000 - 2010 to 39 years
  • Canadians with cystic fibrosis live ~10 years longer than Americans (50.9 years vs 40.6 years)
  • poor prognostic indicators:
    • female sex
    • residence in a northern climate
    • pneumothorax
    • hemoptysis
    • recurrent bacterial infections
    • infection with Pseudomonas cepacia
    • systemic complications

More general terms

• pancreatic disease
• obstructive lung disease
• inborn error of metabolism

Additional terms

• chloride (Cl-) in sweat
• cystic fibrosis (CFTR) genotyping
• cystic fibrosis carrier

Patient information

cystic fibrosis patient information

Database

• OMIM: https://mirror.omim.org/entry/219700