Cystic Fibrosis (Clinical)

Genetics and diagnosis

The defect. Cystic fibrosis (CF) is autosomal recessive, caused by loss-of-function variants in CFTR, a chloride and bicarbonate channel on epithelial surfaces. Secretions in the airways, pancreas, bile ducts, intestine, and vas deferens become dehydrated and thick. F508del, the most common variant, produces a misfolded protein that is degraded before it reaches the cell membrane.

Newborn screening. Every US newborn is screened for immunoreactive trypsinogen (IRT), which leaks from the injured pancreas, usually followed by a CFTR variant panel. A positive screen is not a diagnosis; it triggers a sweat chloride test by pilocarpine iontophoresis.

IRT can be falsely normal in meconium ileus, so any infant with meconium ileus needs sweat or genetic testing even after a negative newborn screen.

Clinical presentations

Salt loss. Heavy sweat losses in hot weather, fever, or exercise produce dehydration with a hyponatremic, hypochloremic, hypokalemic metabolic alkalosis, sometimes the first sign in an infant; salt supplements prevent it. Unlike salt-wasting congenital adrenal hyperplasia (hyperkalemia, acidosis) or pyloric stenosis (vomiting), there is no other obvious source of loss.

Rectal prolapse or nasal polyps in any child, and obstructive azoospermia in a man, warrant a sweat test. Men with CBAVD still produce sperm, so surgical retrieval with IVF can achieve pregnancy.

Infection and chronic therapy

Pathogens by age. S. aureus (including MRSA) and H. influenzae dominate early childhood; mucoid Pseudomonas aeruginosa colonizes most patients by adulthood. A first Pseudomonas isolate is treated with inhaled tobramycin to eradicate it; chronic infection is suppressed with cycled inhaled tobramycin or aztreonam; pulmonary exacerbations get IV dual antipseudomonal therapy. Burkholderia cepacia complex causes rapid decline and spreads between patients, so strict infection control separates people with CF.

Airway clearance. Twice-daily clearance with chest physiotherapy, an oscillating vest, and exercise; dornase alfa, which cleaves the extracellular DNA released by neutrophils to thin sputum (N-acetylcysteine, by contrast, breaks disulfide bonds); inhaled 7% hypertonic saline, which rehydrates the airway surface liquid, preceded by albuterol to prevent bronchospasm; and chronic azithromycin, an anti-inflammatory that reduces exacerbations. Screen for nontuberculous mycobacteria first, because macrolide monotherapy breeds resistant M. abscessus or MAC.

Nutrition. Pancreatic enzymes with every meal and snack, a high-calorie, high-fat diet well above usual needs, vitamins A, D, E, and K, and salt. Nutritional status tracks lung function and survival. Very high enzyme doses cause fibrosing colonopathy.

CFTR modulators. Elexacaftor-tezacaftor-ivacaftor combines two correctors, which improve folding and trafficking so more CFTR reaches the membrane, with a potentiator that holds the channel open. For patients aged 2 and older with at least one F508del or another responsive variant, it lowers sweat chloride, raises FEV1 by roughly 10–14 percentage points, and reduces exacerbations. Monitor liver enzymes, and in children obtain eye exams for cataracts. Ivacaftor alone treats gating variants such as G551D.

Complications

Pattern of decline. Hemoptysis and pneumothorax mark advanced lung disease. DIOS must be distinguished from appendicitis and intussusception, which can also occur in CF; a bubbly fecal mass in the right colon without free air favors DIOS. End-stage lung disease is treated with lung transplantation.