Vignette says a 5 year old male child presents to the pediatric clinic by his parents due to recurrent pulmonary infections and failure to thrive; His mother reports that he has had several episodes of pulmonary infections requiring hospitalizations in the past; He also had a history of meconium ileus (intestinal obstruction) shortly after birth, which was treated with surgery; The mother states that the child has difficulty gaining weight, despite having a healthy appetite; On examination, he appears thin with digital clubbing and barrel shaped chest; Lung auscultation reveals bilateral crackles and wheezing; Sputum culture shows staphylococcus aureus; Chest x-ray shows mild hyperinflation; Sweat chloride test shows elevated chloride levels (i.e. > 60 mmol/L on two occasions after administration of pilocarpine); Genetic testing shows mutation in CFTR gene; Diagnosis?
Diagnosis is Cystic fibrosis.
Pathophysiology:- Mutation of CFTR gene on chromosome 7 (ΔF 508; deletion of phenylalanine) which codes for CFTR protein; CFTR gene encodes an cAMP-activated chloride channel that secretes chloride in lungs & GI tract and reabsorbs chloride in sweat glands that results in:-
1. Decreased chloride secretion and consequently increased sodium (via epithelial Na+ channels (ENaC)) and water resorption, causes abnormally thick mucus secretions into lungs and gastrointestinal tract.
2. Increased chloride secretion in sweat glands.
Clinical Features:-
1. GI features include meconium ileus (failure to pass stool in the first 24 hours after birth) in infants with abdominal distention; Pancreatic insufficiency with steatorrhea and vitamin A, D, E, and K malabsorption; Recurrent pancreatitis; Diabetes mellitus; Weight loss; Distal intestinal obstruction; Biliary cirrhosis; Failure to thrive.
2. Pulmonary features include recurrent respiratory infections (e.g. S aureus [infancy and early childhood], P aeruginosa [adulthood], allergic bronchopulmonary aspergillosis [ABPA]), chronic bronchitis and bronchiectasis), productive cough, dyspnea, chest pain, chronic sinusitis, nasal polyps, nail clubbing.
3. Infertility in males (due to congenital bilateral absence of vas deferens).
4. Heat exhaustion.
Diagnosis:-
1. Elevated sweat chloride test (i.e. > 60 mmol/L on two occasions after administration of pilocarpine).
2. Increased immunoreactive trypsinogen (newborn screening) due to clogging of the pancreatic duct.
3. CXR shows bronchiectasis (reticulonodular pattern on chest x-ray), Pneumothorax, Scarring, Atelectasis, Hyperinflation.
4. Sputum cultures often grow Pseudomonas aeruginosa, Staphylococcus aureus, Haemophilus influenzae.
5. Genetic testing shows mutation in CFTR gene.
6. Spirometry (i.e. pulmonary function test).
Management:-
1. Chest physiotherapy.
2. Antibiotics for infections.
3. Inhaled bronchodilators (e.g. albuterol, salbutamol).
4. Aerosolized dornase alfa (DNase) (mucolytics, breaks down the massive amounts of DNA in respiratory mucus that clogs up the airways); Inhaled hypertonic saline also facilitates mucus clearance; Aerosolized N-acetyl cysteine (mucolytics, breaks disulfide bonds).
5. Pneumococcal and influenza vaccinations.
6. Pancreatic enzyme replacement therapy for pancreatic insufficiency; Fat soluble vitamins supplemention (e.g. A, D, E and K).
7. Combination of lumacaftor or tezacaftor (corrects misfolded proteins and facilitates their transport to cell surface) with ivacaftor (opens chloride channels which improves chloride transport).
8. Lung transplantation.