Origins of cystic fibrosis lung disease

New Engl J Med

At the basic level, we know the genetic cause of cystic fibrosis: it is an autosomal recessive disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). At the clinical level, we know that chronic bacterial airway infection, prominent neutrophilic inflammation, mucus-obstructed airways, and progressive bronchiectasis characterize advanced cystic fibrosis lung disease, which causes most cystic fibrosis morbidity and mortality. Between those two extremes, how loss of CFTR-mediated chloride and bicarbonate transport leads to chronic airway infection has remained uncertain.

Over the past two decades, investigators have studied people with cystic fibrosis, who have disease causing CFTR mutations, at progressively earlier time points. We have learned that, by 3 years of age, bronchiectasis is present in nearly one in three children with cystic fibrosis, although the host defense defects that trigger infection continue to be debated. Even before symptom onset, pulmonary inflammation and infection are often present, although which comes first has been uncertain. As early as 3 months of age, most babies with cystic fibrosis have abnormal chest X-ray computed tomography (CT), although the relative contribution of inflammation, airway remodeling or other factors remains undefined. Moving to even earlier time points might reveal the origins of cystic fibrosis lung disease and thereby change clinical practice.

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