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.
