Cystic Fibrosis & Primary Ciliary Dyskinesia

CFTR and the dehydrated airway

The channel. CFTR is an ATP-binding cassette (ABC) family protein that works as an anion channel for Cl− and HCO3−; it opens when protein kinase A phosphorylates its regulatory domain (a cAMP-driven step) and ATP binds its nucleotide-binding domains. Cystic fibrosis is autosomal recessive, the gene lies on chromosome 7, and the commonest variant, ΔF508 (Phe508del), misfolds so that the protein is retained in the endoplasmic reticulum and degraded before it reaches the membrane. Mutation classes and inheritance problems are covered with the biochemistry of CF.

Opposite jobs in different epithelia. In airway, intestinal, pancreatic and biliary epithelium CFTR secretes Cl− (and HCO3−), and water follows. In the sweat duct it does the reverse, reabsorbing Cl− from primary sweat while ENaC reabsorbs Na+. CF therefore dries out secretions in most organs but leaves sweat abnormally salty — the basis of the sweat test and the reason parents may notice a salty taste when they kiss the baby.

Airway surface liquid. CFTR normally restrains the epithelial Na+ channel (ENaC). When CFTR is lost, Cl− secretion falls and Na+ absorption rises, pulling water out of the airway surface liquid. The periciliary layer collapses, cilia cannot beat through it, and mucus becomes thick and adherent. Stagnant mucus traps bacteria that recruit neutrophils; neutrophil elastase and the DNA released from dead neutrophils damage airway walls and make sputum still more viscous. The excess Na+ absorption also makes the nasal transepithelial potential difference more negative than normal.

Lung disease: bronchiectasis, infection and ABPA

Structural damage. Repeated cycles of obstruction, infection and inflammation produce bronchiectasis that begins in the upper lobes. Physiology is obstructive — reduced FEV1/FVC, increased residual volume and hyperinflation — and FEV1 is the main marker of progression. Complications include hemoptysis from enlarged bronchial arteries, pneumothorax, digital clubbing, hypoxemia with pulmonary hypertension and cor pulmonale. Respiratory failure causes most CF deaths, and lung transplantation is the option for end-stage disease.

Upper airway. Chronic pansinusitis is nearly universal. Nasal polyps in a child should prompt a sweat test; in an adult with asthma, polyps point instead toward aspirin-exacerbated respiratory disease.

Microbiology over time. Infants and young children are colonized first by Staphylococcus aureus (including MRSA) and nontypeable Haemophilus influenzae. Pseudomonas aeruginosa is usually acquired in later childhood or adolescence, intermittently at first; it then switches to a mucoid phenotype that secretes alginate and grows as a biofilm, resisting phagocytosis and antibiotics. Chronic mucoid Pseudomonas is the most common airway pathogen in adults and accelerates the decline in lung function.

Ominous organisms. Burkholderia cepacia complex is intrinsically resistant to many antibiotics, including aminoglycosides and polymyxins, spreads from patient to patient, and can cause cepacia syndrome — fulminant necrotizing pneumonia with bacteremia. For this reason people with CF are kept apart from one another in clinics and at events. Nontuberculous mycobacteria (M. abscessus, M. avium complex), Stenotrophomonas maltophilia and Achromobacter also appear in advanced disease.

Allergic bronchopulmonary aspergillosis (ABPA). Aspergillus fumigatus colonizing the thick mucus of CF or asthma provokes type I (IgE) and type III (immune complex) hypersensitivity rather than tissue invasion. Clues are worsening wheeze, brown mucus plugs, fleeting infiltrates, central bronchiectasis, eosinophilia, a very high total IgE (typically above 1,000 IU/mL), Aspergillus-specific IgE and IgG, and a positive skin test. Systemic glucocorticoids are the mainstay, often with itraconazole to reduce fungal burden.

Diagnosis

Order a sweat test for meconium ileus, nasal polyps in a child, failure to thrive with steatorrhea, recurrent pneumonia or bronchiectasis, or male infertility from absent vasa deferentia.

Extrapulmonary disease

Fat-soluble vitamins. Vitamin A deficiency causes night blindness, D causes rickets or osteomalacia, E causes hemolytic anemia and neuropathy, and K causes bleeding. Treatment is pancreatic enzyme replacement with every meal and snack, ADEK supplements and a high-calorie, high-fat diet.

CF-related diabetes. It combines insulin deficiency (like type 1) with some insulin resistance (like type 2), is rare in young children and becomes common by adulthood; insulin is the treatment.

Meconium ileus. Thick meconium obstructs the terminal ileum, so the newborn fails to pass meconium within 24–48 hours and develops distension and bilious vomiting; contrast enema shows an unused microcolon with inspissated pellets in the ileum. It is almost pathognomonic of CF, whereas Hirschsprung disease is confirmed by rectal suction biopsy.

Male infertility. Spermatogenesis is normal, but absent vasa deferentia and hypoplastic seminal vesicles produce a low-volume ejaculate with no sperm; sperm can be retrieved surgically for IVF with ICSI.

Salt loss. Heavy NaCl losses in sweat during hot weather, fever or exercise, especially in infants, cause volume contraction, which drives a hypochloremic metabolic alkalosis resembling Bartter syndrome.

Treatment

Exacerbations. Acute pulmonary exacerbations are treated with IV antipseudomonal therapy using two drugs, typically a β-lactam plus an aminoglycoside, along with intensified airway clearance. N-acetylcysteine, by contrast, breaks mucin disulfide bonds and is not a standard CF therapy.

CFTR modulators. Correctors (lumacaftor, tezacaftor, elexacaftor) help misfolded F508del protein fold and traffic to the apical membrane; the potentiator ivacaftor then holds the channel open longer. Modulators require liver enzyme monitoring and are affected by CYP3A inducers and inhibitors.

Primary ciliary dyskinesia and Kartagener syndrome

The defect. Motile cilia contain a 9+2 axoneme; dynein arms on the outer microtubule doublets hydrolyze ATP to slide the doublets past one another. PCD is usually autosomal recessive and most often results from mutations in genes for the outer or inner dynein arms (DNAH5 and DNAI1 are common); defects in radial spokes or the central pair are less frequent. Cilia are immotile or beat ineffectively, so mucus is normal in composition but is not moved.

Clinical picture. Unexplained respiratory distress in a term newborn, a daily wet cough from infancy, chronic rhinosinusitis, recurrent otitis media with effusion and conductive hearing loss, and bronchiectasis that favors the middle and lower lobes. Sperm flagella share the axoneme, so men have normal sperm counts but immotile sperm with an intact vas deferens. Women have reduced fertility and more ectopic pregnancies because tubal cilia help move the ovum.

Laterality. Rotating cilia at the embryonic node create a leftward fluid flow that establishes left-right asymmetry. Without it, organ placement is random, so about half of patients have situs inversus. Kartagener syndrome is PCD with situs inversus: dextrocardia, chronic sinusitis and bronchiectasis. Normal situs does not exclude PCD.

Diagnosis and care. Nasal nitric oxide is very low and is used for screening; high-speed video microscopy of ciliary beating, electron microscopy showing absent dynein arms, and genetic testing confirm the diagnosis. The sweat chloride is normal. Management is supportive: airway clearance, prompt antibiotics, ENT and hearing care, and assisted reproduction for infertility.