Cystic fibrosis (CF) is an autosomal recessive genetic
disorder that can shorten life expectancy. It is characterized by pulmonary
symptoms, including obstructive lung disease that worsens over time, sinusitis,
malabsorption due to insufficient pancreatic exocrine function leading to
malnutrition, liver disease such as biliary cirrhosis, and CF-related diabetes
mellitus (CFRD).
CF was a uniformly fatal disease in childhood when first
described in 1938, but today the predicted median survival is 44.4 years.
Over 50% of people with CF are now 18 years and older,
evolving the disease from exclusively a childhood illness to one that affects
adults.
Newborn screening, improved therapies for lung health and
nutrition, and aggressive treatment of respiratory infections and lung
transplantation have improved survival rates.
Newer therapies targeting the genetic defect causing the
disease, expanding to more age and genetic variants, promise continued
improvement in quality of life and overall health.
Epidemiology
CF is a common genetic disorder in Caucasians, with an
incidence of 1:3,200. The incidence varies by race/ethnicity, with lower rates
in Hispanic, African, and Asian populations.
It is estimated that 1 in 35 Americans are CF carriers, and
there are approximately 30,000 affected individuals in the US, with the highest
prevalence in North America, Europe, and Australia.
Around 1,000 new cases are diagnosed annually in the US, and
the incidence is equal in males and females. Since 2010, all US states screen
newborns for CF, resulting in 60% of new diagnoses being made this way
Pathogenesis
CF is a multisystem disorder caused by genetic variants in
the CFTR gene that lead to malfunctioning chloride channels, resulting in the
formation of thick and sticky mucus and various health complications. CF also
results in abnormal chloride channel function in sweat glands, leading to
excessive salt loss.
CF is an autosomal recessive disorder that requires
individuals to inherit two deleterious CFTR variants. There are more than 2,000
different CFTR variants reported that are classified into six distinct groups
that reflect abnormalities of CFTR protein synthesis, structure and function,
with F508del being the most common CF-causing variant.
44.2% of individuals with CF are homozygous for F508del, and
the specific CFTR variants an individual carries determine phenotypic severity
and organ involvement.
DIAGNOSIS
The CFF published consensus guidelines in 2017 establishing
that a diagnosis of CF can be made if an individual has a clinical presentation
consistent with the disease i.e. (1) a positive newborn screening; (2) clinical
features consistent with CF (the presence of characteristic phenotypes such as
of chronic, recurrent sinus and pulmonary disease, nutritional and
gastrointestinal abnormalities, urogenital abnormalities in males (e.g.,
absence of the vas deferens), and/or salt depletion syndromes, or (3) a
positive family history of CF and evidence of CFTR dysfunction (e.g., sweat
chloride concentration ≥60mmol/L).
CF Management
Therapies to
Maintain Optimal Lung Health
CF is marked by the thickening of airway secretions that
cause chronic blockage of mucus, inflammation, and recurring infections that
lead to persistent harm to the airways and lung tissue damage (bronchiectasis).
A chronic cough and production of sputum are symptoms commonly associated with
the condition. The management of respiratory symptoms is directed towards
preserving lung function and preventing the occurrence of bronchiectasis and
destruction of lung parenchyma.
Clearance of
Airway Secretions
Airway clearance therapy (ACT) is crucial for maintaining
lung health in CF patients, as it helps to remove airway mucus, decreasing
bacterial load, and improving gas exchange. Twice daily ACT is recommended for
all CF patients, and frequency is increased during pulmonary exacerbations.
Common ACT modalities include manual percussion, positive expiratory pressure
devices, and high-frequency chest wall oscillation. Exercise is encouraged but
not a substitute for ACT. Nebulized agents such as rhDNase and hypertonic
saline are often used to thin CF mucus during ACT, but the choice of therapy
should be personalized.
Chronic Airway
Infections
Aggressive management of chronic airway infections in CF is
critical for preserving lung function. It involves frequent respiratory
cultures, surveillance for specific pathogens, and eradication therapy when
necessary. Nebulized antibiotics can be used as suppressive therapy to prevent
colonization and reduce the risk of antibiotic resistance. Other organisms that
can impact lung disease are also monitored. CF patients are prone to developing
allergic bronchopulmonary aspergillosis, which requires corticosteroid therapy.
Chronic Airway
Inflammation
Cystic fibrosis lung disease is caused by infection and
inflammation. Corticosteroids are not routinely recommended for CF unless used
for another inflammatory comorbidity. Chronic airway inflammation is managed with
high-dose ibuprofen or azithromycin. Although ibuprofen has proven benefits,
its use is limited by the risk of gastrointestinal bleeding and the need for
monitoring serum levels. Azithromycin is typically given orally three times per
week and has been shown to improve lung function and reduce PEx. However,
screening for mycobacterial infections is recommended before initiating
treatment to avoid the development of resistance.
Therapies to
Maintain Optimal Nutritional Status
Poor growth is an early manifestation of CF due to decreased
intake, malabsorption, and increased metabolic demands. Malnutrition increases
morbidity and mortality in CF. The CFF recommends achieving weight-for-length
at or above the 50th percentile by 2 years old, and maintaining a body mass
index at or above the 50th percentile in children and adolescents aged 2-20
years. Enteral tube feeding should be discussed as an option to optimize
nutritional status. Infants should receive breastmilk if possible or standard
infant formula, supplemented with table salt. Fecal elastase should be measured
to assess pancreatic function, as most individuals with CF have pancreatic
insufficiency, leading to malabsorption, bulky stools, malnutrition, and
failure to thrive.
Pancreatic
Enzyme Replacement Therapy
Pancreatic enzyme replacement therapy (PERT) is recommended
for those with pancreatic insufficiency or symptoms of malabsorption. The
recommended dosage is 2,000-2,500 units/kg of lipase per meal, up to a maximum
of 10,000 units/kg/day. Immobilized lipase cartridges may be used for those on
continuous enteral tube feeding. Exceeding recommended dosages can result in
fibrosing colonopathy. Optimized PERT can help individuals with CF achieve
age-appropriate growth.
Fat-Soluble
Vitamin Replacement Therapy
Pancreatic insufficiency in CF can lead to malabsorption of
fat-soluble vitamins A, D, E, and K. Vitamin deficiencies can cause various
health problems, including night blindness, ocular xerosis, rickets,
osteopenia, osteoporosis, peripheral neuropathy, myopathy, hemolysis, and
coagulopathy. To prevent these complications, CF patients should receive
supplemental vitamins, and their serum vitamin levels should be monitored
annually. The recommended goal for serum 25-hydroxyvitamin D level is at least
30 ng/ml.
CFTR Modulator
Therapies
CFTR modulators are a major advancement in CF treatment as
they directly target the underlying defect in the CFTR protein. Ivacaftor, the
first modulator therapy, is a potentiator that helps improve chloride flow
through the CFTR protein at the cell surface. Correctors, such as lumacaftor
and tezacaftor, help the CFTR protein to form correctly and move to the cell
surface. When added to potentiators, correctors improve the amount of protein that
reaches the cell surface. Triple-combination therapy,
elexacaftor/tezacaftor/ivacaftor (Trikafta), was approved in 2019 and has shown
to be highly effective in improving key measures of disease, including lung
function and quality of life. Amplifiers are currently under development and
are expected to increase the amount of CFTR protein made by a cell.
