• Cystic fibrosis transmembrane regulator (CFTR)
  • Functions as a cyclic AMP-activated chloride channel.
  • Allows for the transport of chloride out of the cell water molecules passively following chloride ion out of the cell, keeping secretions well hydrated.
  • An abnormality in CFTR blocks chloride transport. Inadequate hydration of the cell surface results, causing thick secretions and organ damage.
• In the respiratory system
  • Lungs usually normal early in illness
  • Hypertrophy of mucus-secreting glands
  • Mucus plugging
  • Bronchiectasis
  • Cyst formation (especially in upper lobes)
  • Bacterial colonization
• In the gastrointestinal tract
  • Atrophy of the pancreas
  • Focal biliary cirrhosis of the liver
  • Hypoplasia of the gallbladder

• CFTR gene
  • Located on the long arm of chromosome 7
  • Most common deletion is 3 base pairs, resulting in absence of phenylalanine at codon 508.
  • This F508 mutation is seen in over 70% of the cystic fibrosis population in North America.
  • Currently, over 300 mutations reported

• Most common lethal inherited disease in the white population
• Incidence of abnormalities in the CFTR gene
  • 1:25 individuals of the white race
• Incidence of cystic fibrosis:
  • 1:2500 in white population
  • 1:17,000 in black population
  • 1:10,000 in the population of hispanic origin
  • Less common in African blacks and Asians

• Respiratory complications
  • Recurrent bronchitis and pneumonia
  • Chronic sinusitis
  • Pneumothorax
  • Hemoptysis
• Gastrointestinal complications
  • Pancreatic insufficiency:
    • Patients usually have steatorrhea.
    • Decreased levels of vitamins A, D, E, and K
    • Poor growth
  • Clinically significant hepatobiliary disease
    • Found in 3% of the affected population, cirrhosis of the liver is the most commonly seen complication in patients with advanced liver disease, findings may include:
      • Esophageal varices
      • Splenomegaly
• Cholestasis
• Hypersplenism
  • Reproductive complications:
    • Sterility in 98% of the males due to absence or atresia of the vas deferens
    • Infertility rate for females is 70% to 80% due to thick, tenacious mucus occluding the cervical os.
  • Endocrine complications:
    • Diabetes mellitus seen in up to 12% of patients as they approach the young adult years

• Variable
• Mean lifespan is approximately 29 years
• Course of the disease varies patient to patient

• Recurrent pneumonia or bronchitis
• Severe asthma
• Aspiration pneumonia

• Gastroesophageal reflux
• Celiac sprue
• Protein-losing enteropathy

• Failure to thrive due to:
  • Social problems
  • Poor caloric intake
  • Feeding problems

Question: Have there been respiratory symptoms?
Significance: The most common presenting respiratory symptoms:

Question: Have there been gastrointestinal symptoms?
Significance: Most common presenting gastrointestinal symptoms:

Question: Dietary history?
Significance: Soy bean formula may lead to edema.

Question: Evidence of acute onset of weakness?
Significance: In summer, increased sweating may lead to hyponatremia or hypochloremic metabolic alkalosis.

Finding: Respiratory findings
Significance:

Finding: Other common findings:

Test: Sweat test
Significance: “Gold standard” for the diagnosis of cystic fibrosis; sweat chloride greater than 60 mEq/L is considered abnormal.

Test: Genetic testing
Significance:

Test: Sputum cultures
Significance: Frequently recovered organisms include:

Test: Pulmonary function tests
Significance: Usually reveals obstructive lung disease, although some patients may have a restrictive pattern.

Test: Pancreatic function tests
Significance: Degree of pancreatic disease

Test: 72-hour fecal fat measurement
Significance: Fat malabsorption

Test: Measurement of serum para-aminobenzoic acid (PABA) levels
Significance: Usually reveal evidence of pancreatic insufficiency. One 72 hour fecal fat measurement is the gold standard. Other tests include para-amniobenzoic acid (PABA) level, stool trypsin, serum immune trypsin (IRT)

Test: Stool trypsin levels
Significance: trypsin deficiency

• Chest radiography
  • Often non-specific
  • Typical features include:
    • Hyperinflation
    • Peribronchial thickening
    • Atelectasis
    • Cystic lesions filled with mucus
    • Bronchiectasis (in advanced cases)

• Antibiotic therapy (based on sputum culture results)
  • Oral antibiotics
    • Cephalexin
    • Cefaclor
    • Trimethoprim-sulfamethoxazole
    • Chloramphenicol
    • Ciprofloxacin
    • Inhaled tobramycin in selected patients
  • Intravenous antibiotics
    • To cover Staphylococcus aureus—oxacillin, nafcillin, or vancomycin
    • To cover Pseudomonas aeruginosa and B. cepacia—semisynthetic penicillin or cephalosporin; ticarcillin, piperacillin, or ceftazidime plus aminoglycoside (for synergistic action); gentamicin, tobramycin, or amikacin
    • Severe cases with resistant strains may benefit from imipenem or meropenern
    • Synergistic antibiotic studies should be performed in patients with multi-resistant strains

• Aerosolized bronchodilator therapy (to open airways)
• Mucolytic agents to help break up viscous pulmonary secretions; benefit is controversial. Agents currently available include:
  • N-acetylcysteine
  • rhDNase (Pulmozyme, Genentech, San Francisco, CA)
• Chest physiotherapy with postural drainage. This can be given either manually, or with mucus-clearing devices such as a percussor vest or a Flutter valve.

• Patients with cholestasis may benefit from therapy with ursodieoxycholic acid (Acrisall, Novartis, Summit, NJ)
• Phenobarbital has also been tried, but it interferes with vitamin D metabolism
• Pancreatic enzyme replacement therapy:
  • Used in patients who are pancreatic-insufficient
  • Dosage adjusted for the frequency and character of the stools and for growth pattern
  • Generic substitutes are not bioequivalent to name brands
  • The maximum recommended dose is 2,000 units of lipase/kg/meal
• Vitamin supplements:
  • Multivitamins
  • Fat-soluble vitamin replacement (usually E and K)

• High-calorie diet with nutritional supplements

• Usually lifelong nutritional support required
• Duration of antibiotic therapy is controversial; more chronic use is required as pulmonary function deteriorates.

• Specialized care should be at a cystic fibrosis center.
• Frequency of visits depends on severity of illness: usually every 2 to 4 months.

• Long-term prognosis is poor
• Current mean life span is 29 years
• Due to new antibiotics, maintenance of good pulmonary toilet with chest physiotherapy and bronchodilators, and enzyme replacement therapy. The mean age of survival has been increasing for the past three decades.

• Isolation of hospitalized patient
• Need to isolate from immunocompromised patients, otherwise standard universal precautions. If the affected patient has an antibiotic-resistant organism, then contact precautions.
• Control measures: none

• Most common pitfall is failure to diagnose.
• Not uncommon to delay in making the diagnosis in patients with mild symptoms who do not have evidence of malabsorption.

Q: Should relatives be tested?
A: All siblings should have a sweat test. It is assumed that the parents are healthy carriers if asymptomatic.

Q: How well will a child do?
A: The course of the illness is variable. It is impossible to predict the course of the disease in a specific person.

Q: How should borderline sweat tests be interpreted?
A: Borderline sweat tests should always be repeated. If still borderline, genetic testing should be performed. All results should be correlated with other findings such as physical examination, sputum cultures, pulmonary function, radiographic findings, and nutritional evaluation.

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Fick RB, Stillwell PC. Controversies in the management of pulmonary disease due to cystic fibrosis. Chest 1989;95:1319–1327.

Mouton JW, Kerrebijn KF. Antibacterial therapy in cystic fibrosis. Med Clin North Am 1990;74:837–850.