Cardiorespiratory complications, such as chronic cough, persistent lung infections, obstructive pulmonary disease, and cor pulmonale, constitute the most common cause of death (accounting for approximately 80% of fatalities) in patients who receive follow-up care in most CF centers in the United States. By 18 years of age, 80% of patients with classic CF harbor P. aeruginosa, and 3.5% harbor B. cepacia. With the indiscriminate use of antibiotic prophylaxis, there has been an unfortunate resurgence of resistant strains of Pseudomonas in many patients. Significant liver disease occurs late in the natural history of CF and is foreshadowed by pulmonary and pancreatic involvement; with increasing life expectancy, liver disease is now the third most common cause of death in patients with CF (after cardiopulmonary and transplant-related complications). More extensive DNA sequencing has shown that the spectrum of diseases caused by germline CFTR mutations (either biallelic or in heterozygous carriers) is broader than the “classic” multisystem disease described earlier. For example, some patients suffering from recurrent bouts of abdominal pain and pancreatitis since childhood who were previously classified as having “idiopathic” chronic pancreatitis are now known to harbor biallelic CFTR variants that are distinct from those seen in “classic” CF. Patients with isolated pancreatitis or bilateral absence of vas deferens (see earlier) resulting from CFTR mutations are included under the umbrella of “CFTRopathies.” Similarly, whereas CF carriers were initially thought to be asymptomatic, studies suggest that they have an increased lifetime risk for chronic lung disease (especially bronchiectasis) and recurrent sinonasal polyps. In most cases, the diagnosis of CF is based on persistently elevated sweat electrolyte concentrations (often the mother makes the diagnosis because her infant “tastes salty”), characteristic clinical findings (sinopulmonary disease and gastrointestinal manifestations), or a family history. Sequencing the CFTR gene is the gold standard for diagnosis of CF.
There have been major improvements in the management of acute and chronic complications of CF, including more potent anti-microbial therapies, pancreatic enzyme replacement, and bilateral lung transplantation. Importantly, two new forms of treatment aimed at increasing CFTR protein function in certain CFTR variants have been approved. For example, a group of agents known as CFTR “potentiators” are used in a minority (~3% to 5%) of CF patients who harbor a G155D mutation in the CFTR gene. In this variant, functionally defective CFTR is present in otherwise normal amounts at the cell membrane; the orally bioavailable CFTR “potentiator” partially restores the critical ion transport functions to the defective channel. Another approved drug contains a combination of two agents—one the aforementioned potentiator and the second a drug that increases the transport of the defective Δ508 CFTR protein to the cell membrane. It is too early determine the impact of the emerging molecular therapies on prognosis and survival. Overall, improved management of CF have extended the median life expectancy to close to 40 years and, is steadily changing a lethal disease of childhood into a chronic disease of adults.
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CFisanautosomalrecessivediseasecausedbymutationsintheCFTR geneencodingtheCFtransmembraneregulator.
Theprincipaldefectisofchlorideiontransport,resultinginhighsaltconcentrationsinsweatandinviscousluminalsecretionsinrespiratoryandgastrointestinaltracts.
CFTRmutationscanbesevere(ΔF508),resultinginmultisystemdisease,ormild,withlimiteddiseaseextentandseverity.
Cardiopulmonarycomplicationsconstitutethemostcommoncauseofdeath;pulmonaryinfections,especiallywithresistantPseudomonas orBurkholderia species,arefrequent.Bronchiectasisandright-sidedheartfailurearelong-termsequelae.