Cystic Fibrosis

Essentials of Diagnosis

• Chronic or recurrent cough, sputum production, dyspnea, and wheezing

• Recurrent airways infections or chronic colonization of the airways with

  • Haemophilus influenzae

  • Pseudomonas aeruginosa

  • Staphylococcus aureus

  • Burkholderia cenocepacia

• Bronchiectasis and scarring on chest radiographs

• Airflow obstruction on spirometry

• Pancreatic insufficiency, recurrent pancreatitis, distal intestinal obstruction syndrome, chronic hepatic disease, nutritional deficiencies, or male urogenital abnormalities

• Sweat chloride concentration > 60 mEq/L on two occasions

• Mutations in genes known to cause cystic fibrosis

• Most common fatal hereditary disorder of whites in the United States

• Autosomal recessive disorder due to mutations affecting a membrane chloride channel (the cystic fibrosis transmembrane conductance regulator, or CFTR)

• At least 1000 mutations to the CFTR gene are described, with " ΔF508" accounting for approximately 60% of cases

• Pathophysiology results from production of an abnormal mucous in exocrine glands, which leads to tissue destruction and, in the respiratory tract, impairs mucociliary clearance

• Variety of mutations is reflected in wide range of pulmonary and nonpulmonary manifestations

• Affects 1 in 3200 whites; 1 in 25 is a carrier

Symptoms and Signs

• Disease should be suspected in young adults with a history of chronic lung disease, pancreatitis, or infertility

• Productive cough, decreased exercise tolerance, and recurrent hemoptysis are typical

• Patients also often complain of chronic rhinosinusitis symptoms, steatorrhea, diarrhea, and abdominal pain

• Patients with cystic fibrosis are often malnourished with low body mass index

• Common extrapulmonary manifestations

  • Steatorrhea

  • Diarrhea

  • Abdominal pain

• Nearly all male patients have congenital absence of the vas deferens with azoospermia

• Other findings include

  • Digital clubbing

  • Increased anteroposterior chest diameter

  • Hyperresonance on percussion

  • Apical crackles

Differential Diagnosis

• Chronic obstructive pulmonary disease

• Asthma

• Alpha-1-antiprotease deficiency

• Bronchiolitis

• Celiac disease

• Chronic sinusitis

Laboratory Tests

• Arterial blood gases reveal hypoxemia, with compensated respiratory acidosis in advanced disease

• Pulmonary function tests

  • A mixed obstructive and restrictive pattern

  • Reduced FVC, airflow rates, and total lung capacity

  • Air trapping and reduced diffusion capacity are common

• Genotyping, measurement of nasal membrane potential difference, semen analysis, or assessment of pancreatic function can play a role in diagnosis

• Sputum cultures

  • Frequently show S aureus and P aeruginosa

  • Occasionally show H influenzae, S maltophilia, and B cenocepacia

Imaging Studies

• Hyperinflation is seen early on chest radiographs

• Peribronchial cuffing, mucus plugging, bronchiectasis, atelectasis, small rounded peripheral opacities, and increased interstitial markings are common

• High-resolution CT is the test of choice to confirm bronchiectasis

Diagnostic Procedures

• Chloride sweat test reveals elevated sodium and chloride levels; two tests on different days are required for accurate diagnosis

• A normal sweat chloride test does not exclude the diagnosis

• All patients should undergo CFTR genotyping

Medications

• Inhaled bronchodilators (eg, albuterol, two puffs every 4 hours as needed) should be considered in patients who demonstrate an increase in FEV₁ of > 12% in response to treatment

• Inhaled recombinant human deoxyribonuclease (rhDNase, dornase alpha), 2.5 mg nebulized daily

  • Cleaves extracellular DNA in sputum, decreasing sputum viscosity

  • Leads to improved FEV₁

  • Reduces the risk of cystic fibrosis–related respiratory exacerbations and the need for intravenous antibiotics

• Inhalation of hypertonic saline twice daily has been associated with small improvements in pulmonary function and fewer exacerbations, perhaps due to improved mucus clearance

• Antibiotics are used to treat airway infection based on results of sputum culture and sensitivity testing

• Long-term antibiotics (azithromycin, 500 mg orally three times a week), and various inhaled antibiotics taken 2 to 3 times a day (tobramycin, aztreonam, colistin and levofloxacin) may slow the decline in lung function over time in patients with P aeruginosa

• Ivacaftor, a potentiator of the CFTR channel, works by increasing the time the channel remains open after being activated

• Lumacaftor, tezacaftor, and elexacaftor work by improving CFTR protein folding and cell-surface trafficking

• The combination of elexacaftor, tezacaftor, and ivacaftor has been approved for patients with at least one ∆F508 mutation, a group that includes most patients with cystic fibrosis

Surgery

• Lung transplantation is the only definitive therapy for advanced disease; double-lung or heart-lung transplantation is required

• 3-year survival rates after transplantation are about 55%

Therapeutic Procedures

• Mechanical interventions to clear lower airway secretions

  • Postural drainage

  • Chest percussion or vibration

  • Positive expiratory pressure valve device

  • Flutter valve breathing devices

  • Directed cough

Follow-Up

• Regular assessment of FEV₁

• Regular assessment of nutritional status

Complications

• Pneumothorax and hemoptysis are common

• Cor pulmonale is seen in late disease

• Patients have increased risk of

  • Osteopenia

  • Diabetes mellitus

  • Arthropathies

  • Gastrointestinal malignancies

• Biliary cirrhosis, gallstones, and pancreatitis are seen

• Resistant infections, including methicillin-resistant S aureus and B cenocepacia

Prevention

• Vaccination against pneumococcal infection and annual influenza vaccination are recommended

• Screening of family members and genetic counseling are suggested

Prognosis

• Median survival is to age > 36 years

• Death results from pulmonary infections or from chronic respiratory failure and cor pulmonale

When to Refer

• All patients with suspected or confirmed cystic fibrosis should be referred to a Cystic Fibrosis Center of Excellence for evaluation and treatment recommendations

When to Admit

• Increased cough, sputum production, shortness of breath, decline in FEV₁, weight loss, constitutional symptoms, hemoptysis