Cystic fibrosis: Clinical manifestations of pulmonary disease
- Julie P Katkin, MD
Julie P Katkin, MD
- Associate Professor of Pediatrics
- Baylor College of Medicine
Cystic fibrosis (CF) is a multisystem disease affecting the lungs, digestive system, sweat glands, and the reproductive tract. Patients with CF have abnormal transport of chloride and sodium across secretory epithelia, resulting in thickened, viscous secretions in the bronchi, biliary tract, pancreas, intestines and reproductive system [1,2].
Although the disease is systemic, progressive lung disease continues to be the major cause of morbidity and mortality for most patients. Over a variable time course, ranging from months to decades after birth, individuals eventually develop chronic infection of the respiratory tract with a characteristic array of bacterial flora, leading to progressive respiratory insufficiency and eventual respiratory failure . The rate of progression varies widely, depending in part on genotype (including gene modifiers) as well as environmental factors. Registry data from CF Centers in the United States, Canada, and Europe indicate a median survival of about 40 years (figure 1) . Females with CF appear to have higher morbidity and mortality than males . This "gender gap" is modest but consistent across many populations and is hypothesized to be due to the pro-inflammatory effects of estrogens. (See "Cystic fibrosis: Genetics and pathogenesis".)
Treatment of CF associated-lung disease is undertaken with a variety of modalities, including mechanical airway clearance, antimicrobials, bronchodilators, supplemental oxygen, mucolytics, and a variety of other novel treatments in clinical trials. (See "Cystic fibrosis: Overview of the treatment of lung disease" and "Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection" and "Cystic fibrosis: Investigational therapies".)
PROGRESSION OF PULMONARY DISEASE
Cystic fibrosis (CF) is caused by mutations in a single large gene on chromosome 7 that encodes the cystic fibrosis transmembrane conductance regulator (CFTR) protein [6-8]. CFTR has been shown to function as a regulated chloride channel, which in turn may regulate the activity of other chloride and sodium channels at the cell surface. The net result of these changes is an alteration in the rheology of airway secretions, which become thick and difficult to clear . (See "Cystic fibrosis: Genetics and pathogenesis".)
Pathogens — The chronic airway obstruction caused by viscous secretions is soon followed by colonization with pathogenic bacteria, including Haemophilus influenzae, Staphylococcus aureus, Pseudomonas aeruginosa and Burkholderia cepacia complex species. Methicillin-resistant S. aureus is encountered with increasing frequency in many regions. Other organisms frequently encountered in the CF airways include Stenotrophomonas maltophilia, Achromobacter xylosoxidans and Klebsiella spp, although the contribution of these pathogens to the development of bronchial disease is not always clear. Chronic bacterial infection within the airways occurs in most patients with CF (table 1), and the prevalence of each bacterial type varies with the age of the patient (figure 2). Even among asymptomatic infants identified by newborn screening, there is evidence of subclinical lung disease within the first few months of life [10-12] (see 'Pulmonary function' below). Infection with S. aureus and P. aeruginosa are common even in young children with CF. The presence of P. aeruginosa with a mucoid phenotype is particularly suggestive of CF. Nontuberculous mycobacteria and fungal species such as Aspergillus also contribute to clinical disease in some patients. (See "Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection", section on 'Pathogens'.)
- Rowe SM, Miller S, Sorscher EJ. Cystic fibrosis. N Engl J Med 2005; 352:1992.
- Ratjen F, Döring G. Cystic fibrosis. Lancet 2003; 361:681.
- Gibson RL, Burns JL, Ramsey BW. Pathophysiology and management of pulmonary infections in cystic fibrosis. Am J Respir Crit Care Med 2003; 168:918.
- Cystic Fibrosis Foundation Patient Registry. 2014 Annual Data Report. Bethesda, Maryland Available at: www.cff.org/2014-Annual-Data-Report/ (Accessed on May 01, 2016).
- Sweezey NB, Ratjen F. The cystic fibrosis gender gap: potential roles of estrogen. Pediatr Pulmonol 2014; 49:309.
- Rommens JM, Iannuzzi MC, Kerem B, et al. Identification of the cystic fibrosis gene: chromosome walking and jumping. Science 1989; 245:1059.
- Collins FS. Cystic fibrosis: molecular biology and therapeutic implications. Science 1992; 256:774.
- Drumm ML, Collins FS. Molecular biology of cystic fibrosis. Mol Genet Med 1993; 3:33.
- Wine JJ. The genesis of cystic fibrosis lung disease. J Clin Invest 1999; 103:309.
- Sly PD, Brennan S, Gangell C, et al. Lung disease at diagnosis in infants with cystic fibrosis detected by newborn screening. Am J Respir Crit Care Med 2009; 180:146.
- Stick SM, Brennan S, Murray C, et al. Bronchiectasis in infants and preschool children diagnosed with cystic fibrosis after newborn screening. J Pediatr 2009; 155:623.
- Pillarisetti N, Williamson E, Linnane B, et al. Infection, inflammation, and lung function decline in infants with cystic fibrosis. Am J Respir Crit Care Med 2011; 184:75.
- Davis, PB. Pathophysiology of the lung disease in cystic fibrosis. In: Cystic Fibrosis, Davis, PB (Ed), Marcel Dekker, New York 1993. p.193.
- Hays SR, Ferrando RE, Carter R, et al. Structural changes to airway smooth muscle in cystic fibrosis. Thorax 2005; 60:226.
- Mott LS, Park J, Murray CP, et al. Progression of early structural lung disease in young children with cystic fibrosis assessed using CT. Thorax 2012; 67:509.
- Sly PD, Gangell CL, Chen L, et al. Risk factors for bronchiectasis in children with cystic fibrosis. N Engl J Med 2013; 368:1963.
- Taussig, LM. Cystic fibrosis: An overview. In: Cystic Fibrosis, Taussig, LM (Ed), Thieme-Stratton, New York 1984. p.1.
- Flume PA, Strange C, Ye X, et al. Pneumothorax in cystic fibrosis. Chest 2005; 128:720.
- Flume PA, Yankaskas JR, Ebeling M, et al. Massive hemoptysis in cystic fibrosis. Chest 2005; 128:729.
- Spicuzza L, Sciuto C, Leonardi S, La Rosa M. Early occurrence of obstructive sleep apnea in infants and children with cystic fibrosis. Arch Pediatr Adolesc Med 2012; 166:1165.
- Hiatt P, Eigen H, Yu P, Tepper RS. Bronchodilator responsiveness in infants and young children with cystic fibrosis. Am Rev Respir Dis 1988; 137:119.
- de Jong PA, Ottink MD, Robben SG, et al. Pulmonary disease assessment in cystic fibrosis: comparison of CT scoring systems and value of bronchial and arterial dimension measurements. Radiology 2004; 231:434.
- Farrell PM, Collins J, Broderick LS, et al. Association between mucoid Pseudomonas infection and bronchiectasis in children with cystic fibrosis. Radiology 2009; 252:534.
- Edwards EA, Narang I, Li A, et al. HRCT lung abnormalities are not a surrogate for exercise limitation in bronchiectasis. Eur Respir J 2004; 24:538.
- de Jong PA, Nakano Y, Lequin MH, et al. Progressive damage on high resolution computed tomography despite stable lung function in cystic fibrosis. Eur Respir J 2004; 23:93.
- Cademartiri F, Luccichenti G, Palumbo AA, et al. Predictive value of chest CT in patients with cystic fibrosis: a single-center 10-year experience. AJR Am J Roentgenol 2008; 190:1475.
- de Jong PA, Tiddens HA. Cystic fibrosis specific computed tomography scoring. Proc Am Thorac Soc 2007; 4:338.
- Brody AS, Tiddens HA, Castile RG, et al. Computed tomography in the evaluation of cystic fibrosis lung disease. Am J Respir Crit Care Med 2005; 172:1246.
- Kuo W, Ciet P, Tiddens HA, et al. Monitoring cystic fibrosis lung disease by computed tomography. Radiation risk in perspective. Am J Respir Crit Care Med 2014; 189:1328.
- Puderbach M, Eichinger M, Haeselbarth J, et al. Assessment of morphological MRI for pulmonary changes in cystic fibrosis (CF) patients: comparison to thin-section CT and chest x-ray. Invest Radiol 2007; 42:715.
- Eichinger M, Heussel CP, Kauczor HU, et al. Computed tomography and magnetic resonance imaging in cystic fibrosis lung disease. J Magn Reson Imaging 2010; 32:1370.
- Tepper LA, Ciet P, Caudri D, et al. Validating chest MRI to detect and monitor cystic fibrosis lung disease in a pediatric cohort. Pediatr Pulmonol 2016; 51:34.
- Long FR, Williams RS, Castile RG. Structural airway abnormalities in infants and young children with cystic fibrosis. J Pediatr 2004; 144:154.
- Castile RG, Iram D, McCoy KS. Gas trapping in normal infants and in infants with cystic fibrosis. Pediatr Pulmonol 2004; 37:461.
- Belessis Y, Dixon B, Hawkins G, et al. Early cystic fibrosis lung disease detected by bronchoalveolar lavage and lung clearance index. Am J Respir Crit Care Med 2012; 185:862.
- Linnane BM, Hall GL, Nolan G, et al. Lung function in infants with cystic fibrosis diagnosed by newborn screening. Am J Respir Crit Care Med 2008; 178:1238.
- Harrison AN, Regelmann WE, Zirbes JM, Milla CE. Longitudinal assessment of lung function from infancy to childhood in patients with cystic fibrosis. Pediatr Pulmonol 2009; 44:330.
- Aurora P, Gustafsson P, Bush A, et al. Multiple breath inert gas washout as a measure of ventilation distribution in children with cystic fibrosis. Thorax 2004; 59:1068.
- Gustafsson PM, De Jong PA, Tiddens HA, Lindblad A. Multiple-breath inert gas washout and spirometry versus structural lung disease in cystic fibrosis. Thorax 2008; 63:129.
- Konstan MW, Morgan WJ, Butler SM, et al. Risk factors for rate of decline in forced expiratory volume in one second in children and adolescents with cystic fibrosis. J Pediatr 2007; 151:134.
- Kerem E, Reisman J, Corey M, et al. Prediction of mortality in patients with cystic fibrosis. N Engl J Med 1992; 326:1187.
- Hayes D Jr, Tobias JD, Mansour HM, et al. Pulmonary hypertension in cystic fibrosis with advanced lung disease. Am J Respir Crit Care Med 2014; 190:898.
- PROGRESSION OF PULMONARY DISEASE
- CLINICAL MANIFESTATIONS
- Respiratory symptoms and signs
- Airway reactivity
- RADIOGRAPHIC FINDINGS
- Plain films
- Computed tomography
- Magnetic resonance imaging
- Contrast bronchography
- PULMONARY FUNCTION
- GAS EXCHANGE
- PULMONARY HYPERTENSION
- SOCIETY GUIDELINE LINKS
- INFORMATION FOR PATIENTS