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Clinical Consequences

Effects on the Respiratory System

Respiratory disease from chronic infection is the cause of premature death in more than 95% of patients with CF.²

• Infants with CF are born with normal lung function that remains noraml for the first several weeks following birth
• Within the first 4 weeks of life, evidence of inflammation is present, and by 4 months of age, there is evidence of mucus plugging the bronchioles, inflammation, and bronchiectasis.
• The disease continues to progress as the bronchial walls are further damaged and the airway secretions become infected.
• Eventually, as more areas of the lung are affected by fibrosis (scarring) and bronchiectasis, a number of respiratory complications develop.^2,20

Lung Pathophysiology

Mutation of the CFTR gene causes a defect in mucus clearance, a primary defence mechanism of the lungs.^1,3

• In normal functioning lungs, the rates of sodium absorption and chloride secretion are regulated to adjust the amount of water on the airway surfaces. This progress keeps the mucus thin so that cilia in the lungs can work to clear airway debris.
• In CF, however, it is believed that sodium absorption occurs at a high rate while chloride secretion occurs at a low rate. This lowers the salt and water content of mucus and makes it thick.
• Cilia, therefore, are unable to move and clear the debris from the airway because of the thick, sticky mucus. This leads to infection and the inflammatory cascade to help fight the infection.

Source: Healthline; Cystic Fibrosis.¹⁶

Cycle of Chronic Infection

Cystic fibrotic lungs become permanently colonized with bacteria, most often with Pseudomonas aeruginosa .^2,3

• The body’s immune response is triggered by the presence of bacteria. White blood cells, macrophages, lymphocytes, and neutrophils migrate to the site, kill the bacteria, and die in the process of releasing cytokines. These cytokines are responsible for inflammation in the lung.
• Normally, cilia would clear the cytokines and infection from the lungs. However, in patients with CF, the salt abnormality in airway surface fluid leads to inactivation of naturally occurring antibiotic substances (defensins) and chronic infection in the lungs.
• Patients with CF are difficult to treat because their bodies cannot clear the infection and inflammation, thereby allowing the inflammatory response to remain active.
• The chronic inflammation caused by infection and host response sets up a cycle of long-term damage to the respiratory tract. In fact, failure of both the cardiac and respiratory systems in the leading cause of death in patients with CF.

Source: Braunwald Atlas of Internal Medicine⁴⁷

Respiratory Exacerbations

Quick diagnosis and treatment of respiratory infection is critical to preventing further lung damage in patients with CF. Exacerbations are characterized by an increased frequency and severity of cough, increased sputum production, a change in the colour or appearance of the sputum, shortness of breath (especially with exertion), reduced appetite, and a feeling of chest congestion.^1,3

Although respiratory exacerbations occur at all ages, the frequency increases in adolescents and adults.⁸

Source: Adapted from: Cystic Fibrosis Foundation. Patient Registry Annual Report 2005⁸

Infective Microorganisms

In addition to Pseudomonas aeruginosa infection – the hallmark of lung disease in CF – other, less common pulmonary pathogens are routinely detected in patients with CF.

Pseudomonas aeruginosa⁸

This is the dominant organism in most CF cases, with nearly 60% of patients with CF being culture positive in 2004.

Staphylococcus aureus²

• Staphylococcus aureus is usually the first bacterium isolated from the lungs of infants and young children with CF.
• The organism can cause progressive lung disease and acute pneumonia, leading to death if not treated.
• Staphylococcus aureus that becomes resistant to methicillin, an antibiotic used to treat it, is known as methicillin-resistant Staphylococcus aureus, or MRSA, and is of growing concern.

Haemophilus influezae²

• Haemophilus influezae is found intermittently in the lungs of infants and young children with CF.
• 10% to 15% of patients with CF harbour Haemophilus influezae at any one time.
• The organism rarely establishes long-term colonization.

Burkholderia cepacia complex^1,8

• Burkholderia cepacia complex is a collection of genetically distinct but phenotypically similar bacteria.
• Most patients with CF do not contract bacteria in this group of organisms, but they are important as they may cause a rapid decline in lung function and lead to death. These bacteria are spread by person-to-person contact.

Common Pulmonary Complications

Half of patients with CF first present with pulmonary complications due to lung infection.

Wheezing and Coughing²⁰

Fifty percent of patients present with pulmonary manifestations, often beginning in infancy.

• Recurrent or chronic infections manifested by cough and wheezing are common.
• Cough is the most troublesome complaint, often accompanied by sputum. Gagging, vomiting, and disturbed sleep may also be associated with protracted coughing.

Bronchiectasis

Bronchiectasis, a disorder of the major bronchi and bronchioles, is common in most patients with CF.

• Bronchiectasis develops as a consequence of the persistent obstruction-infection cycle. It is characterized by permanent abnormal dilation and destruction of bronchial walls.
• Bronchiectasis may sometimes cause a portion of the lung to collapse from a loss of air, a condition known as atelectasis.

Digital Clubbing²

Though not a pulmonary complication, digital clubbing develops in most patients with CF.

• The cause of clubbing in chronic infective lung diseases, including CF, is unknown.
• The nail beds thicken and, as a result, the fingers and toes appear clubbed, or wide and round at the tips, in nearly all patients with CF.

Pneumothorax^1,2

Pneumothorax, or the rupture of the alveoli of the lung into the pleural space, is a well-recognized complication of CF. Pneumothorax occurs in 8% to 23% of older patients with CF and has a recurrence rate of 50% to 70%.

• In CF, trapped air (a result of obstruction) may cause alveoli to rupture. This rupture then allows air to enter the pleural space (pneumothorax), collapsing the lung.
• Patients often present with chest pain and difficulty breathing.
• Treatment of a large of symptomatic pneumothorax may require placement of a chest tube to suction out the air. Surgery or chemical sclerosis may be required to prevent recurrences.

Hemoptysis²

Hemoptysis, or blood-streaked sputum, is a serious, life-threatening condition seen more frequently in adult patients with severe lung disease.

• Mild hemoptysis usually resolves upon treatment of the lung infection.
• Massive hemoptysis occurs in less than 10% of adults with CF and is usually associated with an exacerbation of the chronic respiratory infection.

References:
1. Boucher RC. Cystic Fibrosis. In: Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL et al., editors. Harrison's Internal Medicine. 16th ed. New York: McGraw-Hill; 2005. p. 1-9.
2. Aitken M, Fiel SB, Stern RC. Cystic Fibrosis: Respiratory Manifestations. In: Taussig LM, Landau LI, editors. Pediatric Respiratory Medicine. 1st ed. St. Louis: Mosby, Inc.; 1999. p. 1-47
3. Welsh M. Cystic Fibrosis. In: Goldman L, Ausiello D, eds. Cecil Textbook of Medicine. 22nd ed. Philadelphia: WB Saunders; 2004. p. 1-22.
8. Cystic Fibrosis Foundation. Patient Registry Annual Data Report. 2005.
16. Healthline: www.healthline.com Cystic Fibrosis. assessed February 2009
20. Beers MH, Porter RS, Jones TV, Kaplan JL, Berkwits M. Cystic Fibrosis. The Merck Manual 2005;1-10.
47. Braunwald Atlas of Internal Medicine