Cystic fibrosis (CF), the most common life-shortening disease among whites in the United States, affects more than 30,000 people in the United States and 80,000 people worldwide.1 CF occurs in about 1 out of 3,500 births per year in whites and northern Europeans. Although CF is a multiorgan system disease, its effects on the pulmonary system are the leading cause of patient morbidity and mortality.2
PATHOPHYSIOLOGY
CF is caused by a mutation in the CF transmembrane conductance regulator (CFTR) gene. The CFTR protein produced by this gene regulates the movement of chloride and sodium ions across epithelial cell membranes.1 When mutations occur in one or both copies of the gene, ion transport is defective, and results in a buildup of thick mucus throughout the body, leading to respiratory insufficiency, along with many other systemic obstructions and abnormalities (Figure 1).3 A combination of decreased mucociliary clearance and an altered ion transport allow for bacterial colonization of the respiratory tract, most commonly Pseudomonas, Haemophilus influenza, and Staphylococcus aureus. These pathogens cause an overwhelming inflammatory response. Ultimately, chronic infection and this repetitive inflammatory response can lead to airway destruction.4
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FIGURE 1.: Anterior colored chest radiograph showing mucus in the lungs in a patient with CF.
To date, more than 2,000 different CFTR mutations have been reported; the most common one, F508del, accounts for 70% of all mutations.5 CF mutations fall into six classes based on how the defect changes the functionality of the gene (Table 1). The severity of the disease is based on the mutation class.
TABLE 1.: CF classes and defects
1,3PRESENTATION
The classic presentation of CF is respiratory insufficiency or gastrointestinal (GI) disturbances in an infant. Signs of CFTR dysfunction within the GI track normally present earlier than respiratory insufficiencies. Specifically, meconium ileus will by symptomatic before results of neonatal screening are available.6 Due to the recent requirement of newborn screening throughout the United States, CF often is diagnosed before symptoms are noted. The most common symptoms in children are a chronic cough and wheezing associated with malabsorption in the GI tract and failure to thrive.1 Infants may have a meconium ileus, which can help lead to the diagnosis.
Other significant signs and symptoms are nasal polyps, bronchiectasis, pancreatic insufficiency, and sterility.1,3
Common signs and symptoms of CF in the respiratory system include recurrent wheezing or pneumonia, dyspnea on exertion, bronchiolitis, and hemoptysis. Common GI signs and symptoms include abdominal distension, steatorrhea, biliary cirrhosis, and volvulus or intussusception. Genitourinary signs and symptoms include undescended testes, congenital bilateral absence of the vas deferens, and decreased fertility in females.1,3
ASSOCIATED COMPLICATIONS
Complications include CF-related diabetes, spontaneous pneumothorax, and pulmonary hypertension. The most common comorbidity, CF-related diabetes, occurs in 40% to 50% of adults and about 20% of children.7 Guidelines set by the Cystic Fibrosis Foundation (CFF), the Pediatric Endocrine Society (PES), and the American Diabetes Association (ADA) recommend diagnosis of a stable patient based on current ADA guidelines for diabetes. An unstable or acutely ill patient can be diagnosed with a fasting blood glucose greater than 126 mg/dL or a 2-hour postprandial plasma glucose greater than 200 mg/dL, without the classic symptoms of diabetes.7 CF-related diabetes is due to insulin insufficiency, so the only recommended treatment is insulin therapy.7
About 3% of patients will experience a spontaneous pneumothorax during their lifetime; these occur mostly in older adults with end-stage disease.8 Treatment depends on the size of the spontaneous pneumothorax and patient stability. Pulmonary hypertension often is seen in older adults as well, specifically those with advanced lung disease, which is associated with worse outcomes and increased mortality.9 Specific pulmonary hypertension therapy does not benefit these patients because of their advanced disease.10 Delaying disease progression is the best treatment for limiting pulmonary hypertension.
DIAGNOSIS
Initial diagnosis of CF in children is done via the newborn screening test, which has been required in all 50 states since 2010.11 If the test is positive for CF, a conventional sweat test is performed to provide a definitive diagnosis of CF. If CF is confirmed, pulmonary radiographs are used to monitor disease progression. Radiographs also are commonly used as a diagnostic tool for patients with symptoms reflective of CF that have not been previously diagnosed (Figure 2).
FIGURE 2.: Anteroposterior radiographs (A-C) of the lungs of a 12-year-old girl show moderate changes caused by CF, particularly in the right lower quadrant. Cystic bronchiectasis is seen in the right hilar region (B, circle) and varicose bronchiectasis in the perihilar regions bilaterally (C, white arrows). An air-fluid level can be seen on the right side (C, black arrow). A high-resolution CT scan (D) performed 15 months earlier shows bronchiectases in the middle lobe, lower lobes, and the lingula segment. Mucus plugs also can be seen in the right lower lobe (black arrows).
Two algorithms are available for newborn screening: immunoreactive trypsinogen (IRT/DNA and IRT/IRT1/DNA).12 The IRT/DNA algorithm identifies CFTR gene mutations. The algorithm identifies patients with one or two copies of the gene mutation, although it doesn't identify whether the patient has one or both mutations.12 Patients with only one copy of the mutation are identified as carriers of CF; those with two copies are diagnosed with the disease.
A second and newer algorithm, IRT/IRT1/DNA, is clinically significant when the patient has an IRT level greater than 60 ng/mL; the test is repeated within 2 weeks. If a second IRT level is elevated, the patient's DNA is tested for CFTR mutation analysis.12 The newer IRT/IRT1/DNA algorithm has a sensitivity of more than 99.5%, according to Sontag and colleagues.13 Genotyping is commonly performed when patients have an elevated IRT or a positive chloride sweat test. Initial analysis consists of about 100 mutations. If there is no mutation or only one copy of the mutation is identified, a full sequence analysis is performed to determine the exact type of mutation.14
The sweat chloride test, used if the patient has signs and symptoms that raise clinical suspicion for CF, is considered the gold standard for diagnosis of the disease. After initial newborn screening by either the IRT/DNA or IRT/IRT1/DNA algorithm, patients with two elevated IRT levels or who have the CFTR mutation gene are given the sweat chloride test. This test quantitatively measures the amount of chloride in sweat through transdermal administration by iontophoresis of pilocarpine.15 A chloride concentration greater than 60 mmol/L is diagnostic for CF. A repeat chloride test is performed to verify diagnosis.15
Patients diagnosed with CF by sweat test and/or newborn screening and genotyping require extensive follow-up and management for the rest of their lives. Chest radiographs are the most commonly used diagnostic tool to follow disease progression. Radiographs also are extremely useful for diagnosing chronic infection and preventing and managing pulmonary exacerbations. Radiographs also use less radiation than repetitive chest CT scans (Figure 3)—a benefit when managing children with CF.16
FIGURE 3.: Colored scan of an axial section through a patient's lungs (blue) showing mucus in the bronchi (thick orange branching). The heart (orange) is seen at upper right, with a vertebra (white) at lower center.
In patients with early disease, chest radiographs may show hyperinflation and minimal peribronchial thickening. As the disease advances, bronchiectasis, air trapping, and hyperinflation become more prevalent on radiographs.1 Pulmonary exacerbations present with increased sputum production, chronic cough, and lung function decline noted by pulmonary function testing. Bilateral infiltrates may be evident on radiograph.1
The Brasfield score can be used to quantitatively evaluate the progression of pulmonary disease. This score is inversely correlated with disease severity in children and covers the characteristics commonly found in CF exacerbations, including severity, air trapping, linear markings, nodular cystic lesions, and large lesions.16
Pulmonary function tests and arterial blood gas (ABG) analysis also can be used to quantify CF progression. Pulmonary function tests are used to determine the severity of pulmonary exacerbations as well as disease progression of disease; ABG analysis can be useful in early diagnosis as well as determining the severity of exacerbations.14 Patients with declining lung function may exhibit hypoxemia and respiratory acidosis on ABG analysis. As stated by Pedrosa and colleagues, “Greater knowledge of the disease, early diagnosis, follow-up of patients with the aim of controlling pulmonary infections, and appropriate weight gain have contributed significantly to increasing patient survival. Neonatal screening is important for early diagnosis and follow-up care.”16
MANAGEMENT
Multiple treatments can be used for CF depending on disease severity and progression. Conservative treatments including breathing treatments, annual influenza vaccinations, and symptomatic respiratory treatment are used as baseline treatment for all patients. Airway clearance therapy to clear mucus buildup is recommended for all patients to maintain adequate lung function. These treatments include flutter valve therapy, mechanical ventilation, manual chest percussion, and high-frequency vest-assisted chest compression.14 Inhaled hypertonic saline increases the mucociliary clearance and allows for hydration of the respiratory tract. In addition, mucolytics such as dornase alfa can decrease viscosity, allowing easier airway clearance.14 New guidelines released in 2013 show ibuprofen can prevent the loss of lung function in children under age 18 years.17 Ibuprofen is the only anti-inflammatory drug recommended for chronic use in patients with CF. High doses are known to inhibit migration and aggregation of neutrophils throughout the body, including the lungs.18 In patients with CF, a hyperactive inflammatory response with continuous neutrophil influx results in irreversible airway damage.19 Although ibuprofen has a protective effect on the airways, serum levels must be maintained at high doses with a peak plasma concentration of 50 to 100 mcg/mL. Lower doses have been shown to have a proinflammatory effect on mucosa and can lead to disease progression.18 No evidence supports or contradicts chronic use of ibuprofen in patients with CF who are over age 18 years.17 Additionally, research shows evidence of a 3.8% increase in FEV1 in children over age 12 years who use inhaled dry-powder mannitol but this treatment has yet to be approved by the FDA.20
During CF exacerbations, an inhaled beta2-adrenergic agonist is recommended to treat acute hyperresponsiveness.17 Chronic use for lung maintenance is neither recommended nor not recommended.17 Corticosteroids are recommended in patients with asthma or in acute exacerbations, but are not to be used for prophylaxis.21
Antibiotics have been a source of controversy among providers treating patients with CF. As reported by Cohen-Cymberknoh and colleagues, “there is increasing evidence that antibiotic therapy initiated early after the onset of P. aeruginosa infection is an effective strategy to eradicate the organism in the majority of cases and thereby postpone chronic colonization.”22 To reduce exacerbations and maintain lung function, prophylactic treatment with inhaled tobramycin is recommended for patients with persistent P. aeruginosa cultures.17 The 2013 CF pulmonary guidelines recommend oral azithromycin only for patients with persistent P. aeruginosa cultures but not for patients with nontuberculosis mycobacteria, as there is evidence of resistance. Additionally, the anti-inflammatory effects of azithromycin are beneficial in patients with CF.17
Ivacaftor was recently added as a recommendation to the CF pulmonary guidelines in 2013 for use in patients with class III CF mutations.17 Ivacaftor restores chloride channel activity of the CFTR protein at the cell surface, letting the CFTR channel to open properly.17 The drug is useful in patients over age 6 years who have at least one G551D mutation (the third most common mutation associated with CF), or about 4% of patients with CF.23 Ivacaftor is strongly recommended to reduce exacerbations, increase forced expiratory volume (FEV) and lung function, and maintain lung health.17
Though CF has no cure, a lung transplant is the only definitive treatment available for patients with severe bronchiectasis and end-stage lung disease and an FEV less than 30%. The median survival after lung transplant for children is 4.7 years; for adults, 7.8 years.17
Although most treatments are directed at pulmonary manifestations, CF is a multiorgan disease. Other areas requiring treatment include:
- Pancreas. About 85% of patients are treated with pancreatic enzymes to help correct pancreatic insufficiency.17 Enzymes such as pancrelipase help digestion in patients with CF, and vitamin supplementation has been shown to be beneficial to patients with malnutrition and malabsorption.24,25
- Urogenital system. About 99% of males with CF are infertile because congenital bilateral absence of the vas deferens causes obstructive azoospermia.26 During development, the same CFTR mutation influences the development of urogenital organs and can result in abnormalities including absent or atrophic seminal vesicles, vas deferens, epididymis, and ejaculatory ducts. No treatments exist for azoospermia or infertility in men with congenital bilateral absence of the vas deferens; however, because sperm is still produced, it can be harvested from the testes or epididymis for reproduction.27
PROGNOSIS
In the past, CF was thought to be a terminal childhood disease. In certain countries, Canada and Italy, the number of adults over age 18 years with CF is greater than 60% of the total CF population.4 There is a direct correlation between the decade a patient was born and their survival rate. The median survival for patients with CF has increased to age 40 years and is slowly rising, predicted to be age 50 years for children currently diagnosed.28
FUTURE TREATMENT
In addition to the available treatment options, researchers are seeking ways to develop treatments that target the genetic mutation that causes CF. Addressing the genetic mutation ultimately will reduce the treatment burden on patients and provide a higher quality life with greater survival. Drugs are being developed to target and correct the misprocessing of the CFTR protein. Ataluren, now in research trials, may be able to restore the function of the mutated gene and correct chloride channel transport.29
CONCLUSION
Over the years, advancements in the diagnosis and management of CF provided significant improvements in early diagnosis and delayed disease progression. The patient survival rate is increasing, and supportive treatment is becoming more widely available. Primary care providers must be able to recognize symptoms of CF and provide accurate and effective treatment. Also, primary care providers must understand how to monitor and educate patients in order to slow disease progression and help patients achieve the best quality of life.
REFERENCES
1. National Institutes of Health. Genetic testing for cystic fibrosis. National Institutes of Health consensus development conference statement on genetic testing for cystic fibrosis.
Arch Intern Med. 1999;159(14):1529–1539.
2. Cohen-Cymberknoh M, Shoseyov D, Kerem E. Managing cystic fibrosis: strategies that increase life expectancy and improve quality of life.
Am J Respir Crit Care Med. 2011;183(11):1463–1471.
3. Elborn JS. Cystic fibrosis.
Lancet. 2016;388(10059):2519–2531.
4. Bell SC, De Boeck K, Amaral MD. New pharmacological approaches for cystic fibrosis: Promises, progress, pitfalls.
Pharmacol Ther. 2015;145:19–34.
5. Guillot L, Beucher J, Tabary O, et al. Lung disease modifier genes in cystic fibrosis.
Int J Biochem Cell Biol. 2014;52:83–93.
6. O'Sullivan BP, Baker D, Leung KG, et al. Evolution of pancreatic function during the first year in infants with cystic fibrosis.
J Pediatr. 2013;162(4):808–812.
7. Moran A, Brunzell C, Cohen RC, et al. Clinical care guidelines for cystic fibrosis-related diabetes. A position statement of the American Diabetes Association and a clinical practice guideline of the Cystic Fibrosis Foundation, endorsed by the Pediatric Endocrine Society.
Diabetes Care. 2010;33(12):2697–2708.
8. Flume PA, Mogayzel PJ, Robinson KA, et al. Cystic fibrosis pulmonary guidelines: pulmonary complications: hemoptysis and pneumothorax.
Am J Respir Crit Care Med. 2010;182(3):298–306.
9. 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(8):898–905.
10. Tonelli AR. Pulmonary hypertension survival effects and treatment options in cystic fibrosis.
Curr Opin Pulm Med. 2013;19(6):652–661.
11. Cystic Fibrosis Foundation. Testing for cystic fibrosis.
www.cff.org/AboutCF/Testing. Accessed February 13, 2017.
12. Sontag MK, Lee R, Wright D, et al. Improving the sensitivity and positive predictive value in a cystic fibrosis newborn screening program using a repeat immunoreactive trypsinogen and genetic analysis.
J Pediatrics. 2016;175:150–158.
13. Sontag MK, Wright D, Beebe J, et al. A new cystic fibrosis newborn screening algorithm: IRT/IRT1 ↑/DNA.
J Pediatr. 2009;155(5):618–622.
14. Martiniano SL, Hoppe JE, Sagel SD, Zemanick ET. Advances in the diagnosis and treatment of cystic fibrosis.
Adv Pediatr. 2014;61(1):225–243.
15. Rock MJ, Makholm L, Eickhoff J. A new method of sweat testing: the CF Quantum sweat test.
J Cyst Fibros. 2014;13(5):520–527.
16. Pedrosa JF, Da Cunha Ibiapina C, Alvim CG, et al. Pulmonary radiographic findings in young children with cystic fibrosis.
Pediatr Radiol. 2015;45(2):153–157.
17. Mogayzel PJ Jr, Naureckas ET, Robinson KA, et al. Cystic fibrosis pulmonary guidelines. Chronic medications for maintenance of lung health.
Am J Respir Crit Care Med. 2013;187(7):680–689.
18. Lands LC, Dauletbaev N. High-dose ibuprofen in cystic fibrosis.
Pharmaceuticals (Basel). 2010;3(7):2213–2224.
19. Lands LC, Stanojevic S. Oral non-steroidal anti-inflammatory drug therapy for lung disease in cystic fibrosis.
Cochrane Database Syst Rev. 2013;(6):CD001505.
20. Ong T, Ramsey BW. Modifying disease in cystic fibrosis: current and future therapies on the horizon.
Curr Opin Pulm Med. 2013;19(6):645–651.
21. Bhatt JM. Treatment of pulmonary exacerbations in cystic fibrosis.
Eur Respir Rev. 2013;22(129):205–216.
22. Cohen-Cymberknoh M, Shoseyov D, Kerem E. Managing cystic fibrosis: strategies that increase life expectancy and improve quality of life.
Am J Respir Crit Care Med. 2011;183(11):1463–1471.
23. Whiting P, Al M, Burgers L, et al. Ivacaftor for the treatment of patients with cystic fibrosis and the G551D mutation: a systematic review and cost-effectiveness analysis.
Health Technol Assess. 2014;18(18):1–106.
24. Trapnell BC, Strausbaugh SD, Woo MS, et al. Efficacy and safety of PANCREAZE® for treatment of exocrine pancreatic insufficiency due to cystic fibrosis.
J Cyst Fibros. 2011;10(5):350–356.
25. Munck A. Nutritional considerations in patients with cystic fibrosis.
Expert Rev Respir Med. 2010;4(1):47–56.
26. Ahmad A, Ahmed A, Patrizio P. Cystic fibrosis and fertility.
Curr Opin Obstet Gynecol. 2013;25(3):167–172.
27. Ong T, Marshall SG, Karczeski BA, et al. Cystic fibrosis and congenital absence of the vas deferens.
GeneReviews, February 2, 2017.
28. MacKenzie T, Gifford AH, Sabadosa KA, et al. Longevity of patients with cystic fibrosis in 2000 to 2010 and beyond: survival analysis of the cystic fibrosis foundation patient registry.
Ann Intern Med. 2014;161(4):233–241.
29. Wainwright CE. Ivacaftor for patients with cystic fibrosis.
Expert Rev Respir Med. 2014;8(5):533–538.
