CME

Keep them breathing: Cystic fibrosis

pathophysiology, diagnosis, and treatment
Sheena D. Brown, PhD, MSCR; Rachel White, MMSc, PA-C; Phil Tobin, DHSc, PA-C

ABSTRACT
Cystic fibrosis (CF) affects more than 30,000 people in the
United States and 80,000 people worldwide. This life-threat-
ening genetic disorder causes a buildup of thick, viscous
mucus secretions in various organ systems, most commonly
the gastrointestinal, pulmonary, and genitourinary systems.
This article reviews the clinical manifestations, diagnosis,
and monitoring of patients with CF as well as guidelines for
management and emerging pharmacologic treatments.
Keywords: cystic fibrosis, newborn screening, chloride
sweat test, bronchiectasis, Brasfield score, airway clearance

© PHOTOSTOCK-ISRAEL | SCIENCE SOURCE

therapy

Learning objectives
Describe the pathophysiology, clinical presentation,
and complications of CF.
Explain algorithms for newborn screening for CF.
Discuss available treatment options for patients
with CF.
FIGURE 1. Anterior colored chest radiograph showing mucus in
the lungs in a patient with CF.

C
ystic 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
Sheena D. Brown is a clinical assistant professor at Mercer University
in Atlanta, Ga. Rachel White practices at Precision Bone and Joint in
Austin, Tex. Phil Tobin is director and an associate professor in the PA
program at Touro University Nevada. The authors have disclosed no
potential conflicts of interest, financial or otherwise.
DOI:10.1097/01.JAA.0000515540.36581.92
Copyright © 2017 American Academy of Physician Assistants
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 insuf-
ficiency, 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 over-
whelming inflammatory response. Ultimately, chronic
infection and this repetitive inflammatory response can
lead to airway destruction.4
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.

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Copyright © 2017 American Academy of Physician Assistants

CME

Key points TABLE 1. CF classes and defects1,3

Cystic fibrosis occurs in 1 out of 3,500 births of Caucasians
and northern Europeans.
All newborns should be screened using the new algorithms
with reflex sweat chloride testing to provide a more
sensitive test for diagnosis of CF.
The median survival for individuals with CF has increased
to 40 years of age in the United States.
CF patients with persistent P. aeruginosa cultures should
be prescribed inhaled tobramycin prophylactically to
reduce exacerbations and maintain lung function.
Recently approved treatment options, such as Ivacaftor,
are now recommended for use in Class III mutations.
PRESENTATION
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, meco-
nium 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 com-
mon symptoms in children are a chronic cough and wheez-
ing 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, steator-
rhea, 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 Asso-
ciation (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 clas-
sic symptoms of diabetes.7 CF-related diabetes is due to
insulin insufficiency, so the only recommended treatment
is insulin therapy.7
Class Mutation defect Specific effect of mutation class
I Lack of CFTR No functioning CFTR chloride
synthesis channels
II Defective protein CFTR is destroyed in the cell.
processing CFTR does not reach cell
surface
III Defective channel CFTR reaches cell surface but
regulation does not properly open for
chloride transport
IV Defective chloride CFTR function is poor and
conduction chloride conduction is defective
V Reduced amount Decreased production of CFTR
of CFTR protein
VI Increased CFTR is functional but unstable
turnover of CFTR at cell surface, and is removed
at cell surface and destroyed
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 mon-
itor 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).
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 clin-
ically 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

24 www.JAAPA.com Volume 30 • Number 5 • May 2017

Copyright © 2017 American Academy of Physician Assistants

 Keep them breathing: Cystic fibrosis pathophysiology, diagnosis, and treatment

algorithm has a sensitivity of

more than 99.5%, according to
Sontag and colleagues.13 Geno-
typing 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 symp-
toms that raise clinical suspicion
for CF, is considered the gold

SOURCE: NATIONAL INSTITUTES OF HEALTH

standard for diagnosis of the dis-
ease. 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 quantita-
tively measures the amount of
chloride in sweat through trans-
dermal administration by ionto-
phoresis of pilocarpine.15 A FIGURE 2. Anteroposterior radiographs (A-C) of the lungs of a 12-year-old girl show moderate
chloride concentration greater changes caused by CF, particularly in the right lower quadrant. Cystic bronchiectasis is seen in
than 60 mmol/L is diagnostic for 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
CF. A repeat chloride test is per- CT scan (D) performed 15 months earlier shows bronchiectases in the middle lobe, lower lobes,
formed to verify diagnosis.15 and the lingula segment. Mucus plugs also can be seen in the right lower lobe (black arrows).
Patients diagnosed with CF
by sweat test and/or newborn screening and genotyping tions, including severity, air trapping, linear markings,
require extensive follow-up and management for the rest nodular cystic lesions, and large lesions.16
of their lives. Chest radiographs are the most commonly Pulmonary function tests and arterial blood gas (ABG)
used diagnostic tool to follow disease progression. Radio- analysis also can be used to quantify CF progression.
graphs also are extremely useful for diagnosing chronic Pulmonary function tests are used to determine the sever-
infection and preventing and managing pulmonary exac- ity of pulmonary exacerbations as well as disease progres-
erbations. Radiographs also use less radiation than repet- sion of disease; ABG analysis can be useful in early
itive chest CT scans (Figure 3)—a benefit when managing diagnosis as well as determining the severity of exacerba-
children with CF.16 tions.14 Patients with declining lung function may exhibit
In patients with early disease, chest radiographs may hypoxemia and respiratory acidosis on ABG analysis. As
show hyperinflation and minimal peribronchial thickening. stated by Pedrosa and colleagues, “Greater knowledge of
As the disease advances, bronchiectasis, air trapping, and the disease, early diagnosis, follow-up of patients with the
hyperinflation become more prevalent on radiographs.1 aim of controlling pulmonary infections, and appropriate
Pulmonary exacerbations present with increased sputum weight gain have contributed significantly to increasing
production, chronic cough, and lung function decline noted patient survival. Neonatal screening is important for early
by pulmonary function testing. Bilateral infiltrates may be diagnosis and follow-up care.”16
evident on radiograph.1
The Brasfield score can be used to quantitatively evalu- MANAGEMENT
ate the progression of pulmonary disease. This score is Multiple treatments can be used for CF depending on disease
inversely correlated with disease severity in children and severity and progression. Conservative treatments includ-
covers the characteristics commonly found in CF exacerba- ing breathing treatments, annual influenza vaccinations,

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CME
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 compres-
sion.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 Ibupro-
fen 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 through-
out 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 evi-
dence 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
Median survival for patients
with CF is slowly rising.
During CF exacerbations, an inhaled beta2-adrenergic
agonist is recommended to treat acute hyperresponsive-
ness.17 Chronic use for lung maintenance is neither recom-
mended nor not recommended.17 Corticosteroids are
recommended in patients with asthma or in acute exacer-
bations, 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 per-
sistent P. aeruginosa cultures but not for patients with
nontuberculosis mycobacteria, as there is evidence of
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Copyright © 2017 American Academy of Physician Assistants
© JAMES CAVALLINI | SCIENCE SOURCE
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.
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 pan-
creatic 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 malab-
sorption.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 develop-
ment, the same CFTR mutation influences the development
of urogenital organs and can result in abnormalities includ-
ing absent or atrophic seminal vesicles, vas deferens,
Volume 30 • Number 5 • May 2017
 Keep them breathing: Cystic fibrosis pathophysiology, diagnosis, and treatment
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 man-
agement 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 pro-
viders must understand how to monitor and educate
patients in order to slow disease progression and help
patients achieve the best quality of life. JAAPA
Earn Category I CME Credit by reading both CME articles in this issue,
reviewing the post-test, then taking the online test at http://cme.aapa.
org. Successful completion is defined as a cumulative score of at least
70% correct. This material has been reviewed and is approved for 1 hour
of clinical Category I (Preapproved) CME credit by the AAPA. The term of
approval is for 1 year from the publication date of May 2017.
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.
JAAPA Journal of the American Academy of Physician Assistants
Copyright © 2017 American Academy of Physician Assistants
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 pancre-
atic 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 insuffi-
ciency 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.
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