Cystic Fibrosis

Etiology
Cystic fibrosis (CF) is an autosomal recessive disorder caused by a mutation in the genes that
code for chloride transport. This is known as the cystic fibrosis transmembrane conductance
regulator (CFTR). Mutations in the CFTR gene damage chloride and water transport across the
apical surface of epithelial cells in exocrine glands throughout the body. This leads to abnormally
thick mucus in the lungs, as well as damage to the pancreas, liver, sinuses, intestines, and
genitourinary tract. They all clog up.
Neutrophils in CF dump tons of DNA into airway secretions, clogging them up.

Damaged mucus clearance decreases the ability to get rid of inhaled bacteria.

Presentation
Over one-third of CF patients are adults. Look for a young adult with chronic lung disease (cough,
sputum, hemoptysis, bronchiectasis, wheezing, and dyspnea) and recurrent episodes of infection.
Sinus pain and polyps are common.
Lung disease accounts for 95% of deaths in CF.

Gastrointestinal Involvement
• Meconium ileus in infants with abdominal distention
• Pancreatic insufficiency (in 90%) with steatorrhea and vitamin A, D, E, and K
malabsorption
• Recurrent pancreatitis
• Distal intestinal obstruction
• Biliary cirrhosis
Islets are spared. Beta cell function is normal until much later in life.

Genitourinary Involvement
Men are often infertile; 95% have azoospermia, with the vas deferens missing in 20%. Women
are infertile because chronic lung disease alters the menstrual cycle and thick cervical mucus
blocks sperm entry.

Diagnostic Tests
The most accurate test is an increased sweat chloride test. Pilocarpine increases acetylcholine
levels which increases sweat production. Chloride levels in sweat above 60 mEq/L on repeated
testing establishes the diagnosis.
• Genotyping with CFTR is not as accurate as finding an increased sweat chloride level.
This is because there are so many different types of mutations leading to CF.

Additional Diagnostic Tests

Chest x-ray and CT: There is no single abnormality on imaging of the chest to confirm a
diagnosis of CF. Findings include:
 • Bronchiectasis
• Pneumothorax
• Scarring
• Atelectasis
• Hyperinflation

Arterial blood gas may show hypoxemia and, in advanced disease, a respiratory acidosis.

PFTs show mixed obstructive and restrictive patterns; decrease in FVC and total lung capacity;
and decreased diffusing capacity for carbon monoxide.

Sputum culture:
• Nontypable Haemophilus influenzae
• Pseudomonas aeruginosa
• Staphylococcus aureus
• Burkholderia cepacia

Treatment
1. Antibiotics are routine. See the choices listed for bronchiectasis. Eliminating colonization
is difficult and sputum culture is essential to guide therapy. Inhaled aminoglycosides as a
treatment method are almost exclusively limited to CF.
2. Inhaled recombinant human deoxyribonuclease (rhDNase). This breaks down the massive
amounts of DNA in respiratory mucus that clogs up the airways.
3. Inhaled bronchodilators such as albuterol
4. Pneumococcal and influenza vaccinations
5. Lung transplantation is used only in advanced disease not responsive to the therapy
previously listed.
6. Ivacaftor combined with lumacaftor increases the activity of CFTR in the 5% of patients
who have a specific mutation. Tezacaftor is an alternative.
Bronchiectasis
Definition
Bronchiectasis is an uncommon disease from chronic dilation of the large bronchi. This is a
permanent anatomic abnormality that cannot be reversed or cured. Bronchiectasis is uncommon
because of better control of infections of the lung which lead to the weakening of the bronchial
walls.

Etiology
The single most common cause of bronchiectasis is cystic fibrosis, which accounts for half of
cases. Other causes are:
• Infections: tuberculosis, pneumonia, abscess
• Panhypogammaglobulinemia and immune deficiency
• Foreign body or tumors
• Allergic bronchopulmonary aspergillosis (ABPA)
• Collagen-vascular disease such as rheumatoid arthritis

Presentation/“What Is the Most Likely Diagnosis?”

Recurrent episodes of very high volume purulent sputum production are the key to the suggestion
of the diagnosis. Hemoptysis can occur. Dyspnea and wheezing are present in 75% of cases. Other
findings are:
• Weight loss
• Anemia of chronic disease
• Crackles on lung exam
• Clubbing is uncommon
• Dyskinetic cilia syndrome

Diagnostic Tests
The best initial test is a chest x-ray that shows dilated, thickened bronchi, sometimes with “tram-
tracks,” which is the thickening of the bronchi.
It is impossible to diagnose bronchiectasis without an imaging study of the lungs such as
a CT scan.

The most accurate test is a high-resolution CT scan.

Figure 4.3: Bronchiectasis with Widening of the Bronchi in Multiple Areas. Source:
Leyla Medinasab, MD.

Sputum culture is the only way to determine the specific bacterial etiology of the recurrent episodes
of infection.

Treatment
1. Chest physiotherapy (“cupping and clapping”) and postural drainage are essential for
dislodging plugged-up bronchi.
2. Treat each episode of infection as it arises. Use the same antibiotics as for exacerbations of
COPD. The only difference is that inhaled antibiotics seem to have some efficacy and a specific
microbiologic diagnosis is preferred since Mycobacterium avium intracellulare (MAI) can be
found.
3. Rotate antibiotics, 1 weekly each month.
4. Surgical resection of focal lesions may be indicated.
5. Dornase alfa is used for bronchiectasis arising from cystic fibrosis. Dornase is an enzyme
that cleaves DNA in sputum, reducing viscosity.
6. Treatments that are not clearly effective are beta agonists and pulmonary rehabilitation.
Lung Cancer
The most important question for lung cancer is who should be treated with surgery?

The size of the lesion is not the most important factor in whether or not the lesion is resectable. If
the lesion is large, but is surrounded by normal lung and there is enough remaining lung function
post resection, then surgery is still possible.
Screen for lung cancer annually with low-dose chest CT in those with:
• 30 pack-year smoking history
• Age 55–80

Surgery is not possible in these cases:

• Bilateral disease or lymph nodes involved on opposite side
• Malignant pleural effusion
• Heart, carina, aorta, or vena cava is involved

Small cell cancer is considered unresectable in 95% of cases because it is metastatic or spread
outside one lung.

Treatment
When the question describes lung cancer that tests positive for the programmed death (PD)
biomarker (not the specific histology), the answer is pembrolizumab and nivolumab. These PD
inhibitors are more effective and better tolerated than platinum therapy for non–small cell lung
cancer.