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Pathogenesis of Early Lung Disease in Cystic Fibrosis: A Window of Opportunity To Eradicate Bacteria

Timothy D. Starner, MD; and Paul B. McCray Jr., MD
[+] Article, Author, and Disclosure Information

From University of Iowa, Iowa City, Iowa.

Grant Support: None.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Paul B. McCray Jr., MD, or Timothy D. Starner, MD, Department of Pediatrics, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242.

Current Author Addresses: Drs. Starner and McCray: Department of Pediatrics, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242.

Ann Intern Med. 2005;143(11):816-822. doi:10.7326/0003-4819-143-11-200512060-00010
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Second only to sickle-cell anemia, cystic fibrosis is the most common genetic disease causing early death (1). Although pulmonary disease causes most of the morbidity and mortality associated with cystic fibrosis, the lungs are thought to be anatomically normal at birth (2). In patients with cystic fibrosis, progression of lung disease is insidious, and patients may be relatively asymptomatic before irreversible changes and chronic bacterial colonization occur. Cough is the predominant symptom in the early stages of cystic fibrosis, occurring in as many as 50% of patients by 10 months of age (3); however, many patients do not have pulmonary symptoms. The first detectable evidence of lung disease in patients with cystic fibrosis is infection and/or inflammation in bronchoalveolar lavage fluid, denoted by elevated counts of interleukin-8 and neutrophils and the presense of microorganisms (47). However, detecting bacteria is complicated by regional heterogeneity of inflammation and infection (89). Haemophilus influenzae, Staphylococcus aureus, and P. aeruginosa are the most prevalent early pathogens, and most patients have colonization with at least 1 of these bacteria by 1 year of age (1011). Early infections with P. aeruginosa can be transient, and approximately half clear spontaneously (1214). However, by their teenage years, most patients have colonization with P. aeruginosa(11).

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Figure 1.
Pathogenesis of lung disease in patients with cystic fibrosis.

Regardless of the initial inflammatory insult or defective process, once this cycle is started, it will lead to all elements being increasingly perturbed. Several interconnected cycles perpetuate and further impair host defense, leading to persistent bacterial infections and progressive lung disease. Possible primary factors resulting from mutant cystic fibrosis transmembrane conductance regulator also are indicated by asterisks. ASL = airway surface liquid.

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Figure 2.
Diagram showing the relationship between the window of opportunity for eradication ofPseudomonas aeruginosaand the progression of lung disease over time.

Inflammation may be reversible during the transient infection period, but increasing inflammation and irreversible lung damage occur with chronic and mucoid infections. There is evidence that some inflammation and lung damage may occur at times earlier than indicated. “100%” indicates the top of the y-axis for the Lung Function box.

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