Cystic Fibrosis
Cystic fibrosis (CF) is a life-limiting, autosomal recessive genetic disorder characterized by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a chloride channel involved in the regulation of salt and water transport across epithelial surfaces. The most common mutation is the F508del, but over 2,000 variants have been identified. The defective or absent CFTR protein leads to impaired chloride and bicarbonate transport, resulting in thick, viscous secretions in various organs, most notably the lungs, pancreas, gastrointestinal tract, and reproductive system. This pathogenesis underlies the hallmark clinical manifestations: chronic respiratory infections, progressive lung damage, pancreatic insufficiency, malnutrition, and male infertility. The accumulation of thick mucus in the airways promotes persistent bacterial colonization and inflammation, leading to bronchiectasis and respiratory failure, which is the primary cause of morbidity and mortality. Beyond the pulmonary system, CF affects digestive function due to pancreatic duct obstruction, resulting in malabsorption and growth failure, and can also cause hepatobiliary and endocrine complications.
Classic CF is defined by the presence of two severe CFTR mutations leading to minimal or absent CFTR function. Patients typically present in early childhood with chronic sinopulmonary disease, exocrine pancreatic insufficiency, elevated sweat chloride levels, and male infertility. The clinical course is characterized by recurrent pulmonary infections, failure to thrive, and complications such as diabetes and liver disease.
Atypical CF, also referred to as non-classic or mild CF, is associated with at least one CFTR mutation that allows for residual protein function. Patients may present later in childhood or adulthood with milder or isolated symptoms, such as recurrent sinusitis, bronchiectasis, or congenital bilateral absence of the vas deferens (CBAVD) without significant pulmonary or gastrointestinal involvement. Sweat chloride levels may be normal or borderline, and pancreatic function is often preserved.
CFTR-related disorders encompass conditions caused by CFTR dysfunction that do not meet the full diagnostic criteria for CF. These include isolated male infertility due to CBAVD, idiopathic chronic pancreatitis, and some cases of bronchiectasis. These individuals may carry one or two CFTR mutations but lack the multi-system involvement characteristic of classic CF.
Cystic fibrosis is one of the most common life-shortening autosomal recessive disorders among individuals of European descent, with an estimated incidence of 1 in 2,500 to 3,500 live births in Caucasian populations. The carrier frequency in these populations is approximately 1 in 25. The prevalence is substantially lower in individuals of African, Asian, or Hispanic ancestry, with incidences ranging from 1 in 15,000 to 1 in 100,000 live births. Advances in newborn screening, improved clinical management, and the advent of targeted therapies have significantly increased life expectancy, with median survival now exceeding 40 years in many countries. The global burden of CF varies, with the highest rates observed in North America, Europe, and Australia. Despite improvements in survival, CF remains associated with considerable morbidity, frequent hospitalizations, and a significant impact on quality of life.
Diagnosis of cystic fibrosis requires a combination of clinical features consistent with CF and evidence of CFTR dysfunction. The gold standard diagnostic test is the quantitative pilocarpine iontophoresis sweat chloride test, with values of 60 mmol/L or greater considered diagnostic in the appropriate clinical context. Intermediate values (30–59 mmol/L) may warrant further evaluation. Newborn screening programs typically employ immunoreactive trypsinogen (IRT) assays, followed by DNA analysis for common CFTR mutations if IRT is elevated. Genetic testing can identify pathogenic variants in the CFTR gene, and identification of two disease-causing mutations confirms the diagnosis, especially when sweat chloride results are equivocal. Ancillary diagnostic approaches include assessment of nasal transepithelial potential difference and intestinal current measurements, which evaluate CFTR function in vivo. Clinical criteria supportive of diagnosis include chronic sinopulmonary disease, exocrine pancreatic insufficiency, recurrent respiratory infections, failure to thrive, and a family history of CF. Early diagnosis through newborn screening and genetic counseling is critical for optimizing outcomes and facilitating timely interventions.
Therapeutic strategies for cystic fibrosis include several pharmacological agents targeting different aspects of the disease. The combination of vanzacaftor, tezacaftor, and deutivacaftor is utilized as a CFTR modulator therapy designed to enhance the function of defective CFTR protein in individuals with specific mutations. Another triple combination therapy, elexacaftor, tezacaftor, and ivacaftor, acts by improving the processing, trafficking, and gating of the CFTR protein, providing clinical benefits in lung function and quality of life for patients with at least one F508del mutation. Dornase alpha, a recombinant human DNase I, is administered via inhalation to degrade extracellular DNA in airway secretions, thereby reducing mucus viscosity and improving pulmonary function. The dual therapy of tezacaftor and ivacaftor is prescribed to increase CFTR protein activity at the cell surface and is indicated for patients with certain responsive mutations. Lumacaftor/ivacaftor is another combination that corrects the folding and function of the CFTR protein, particularly in individuals homozygous for the F508del mutation. Ivacaftor, as a standalone agent, serves as a CFTR potentiator that enhances chloride transport in patients with gating mutations. For the management of pulmonary infections, aztreonam L-lysine is an inhaled antibiotic targeting Pseudomonas aeruginosa and other Gram-negative pathogens commonly colonizing the CF airway, while levofloxacin is a fluoroquinolone antibiotic employed in the treatment of acute and chronic respiratory infections associated with cystic fibrosis. Dornase alfa is also used to decrease mucus accumulation and improve airway clearance, further supporting respiratory function.
| Structure | Generic Name | CAS Registry Number | Molecular Formula | Molecular Weight |
|---|---|---|---|---|
| vanzacaftor/tezacaftor/deutivacaftor | ||||
| elexacaftor/tezacaftor/ivacaftor | ||||
| dornase alpha | ||||
| tezacaftor/ivacaftor | ||||
| lumacaftor/ivacaftor | ||||
 | ivacaftor (Prop INN; USAN) | 873054-44-5 | C24 H28 N2 O3 | 392.491 |
 | aztreonam L-lysine (USAN); aztreonam lysinate | 827611-49-4 | C13 H17 N5 O8 S2 . C6 H14 N2 O2 | 581.62 |
| dornase alfa (Rec INN; USAN; BAN); dornase alpha | 143831-71-4 | |||
 | levofloxacin (Rec INN; USAN) | 100986-85-4 | C18 H20 F N3 O4 | 361.368 |
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