Cystic Fibrosis

A 5-year-old boy presents with recurrent pulmonary infections and failure to thrive. He had meconium ileus shortly after birth. Despite a good appetite, he has poor weight gain. Examination shows digital clubbing, a barrel-shaped chest, bilateral crackles, and wheezing. Sputum culture grows Staphylococcus aureus. Chest X-ray shows hyperinflation. Sweat chloride is ≥60 mmol/L on two occasions, and genetic testing identifies a CF-causing CFTR variant. Diagnosis?

The diagnosis is cystic fibrosis.

1. Definition

Cystic fibrosis is an autosomal recessive multisystem disorder caused by pathogenic variants in the CFTR gene, resulting in abnormal chloride and bicarbonate transport and thick, dehydrated secretions.

2. Pathophysiology

1.      Mutation in the CFTR gene on chromosome 7. F508del is the most common CF-causing variant, although its frequency varies among populations.

2.      The CFTR protein is a cAMP-regulated chloride and bicarbonate channel.

3.      Effects:

1.      Lungs and GI tract

§  Decreased chloride and bicarbonate secretion

§  Thick, dehydrated mucus

§  Impaired mucociliary clearance, obstruction, and recurrent infection

2.      Sweat glands

§  Decreased chloride reabsorption

§  Increased chloride concentration in sweat

3. Clinical Features

3.1 Pulmonary

1.      Recurrent respiratory infections

o    Common organisms include Staphylococcus aureus, Haemophilus influenzae, and Pseudomonas aeruginosa

o    S. aureus is common in younger children, while chronic Pseudomonas infection becomes more prevalent with increasing age and disease severity

2.      Chronic cough and sputum production

3.      Bronchiectasis

4.      Wheezing and obstructive lung disease

5.      Digital clubbing

6.      Chronic sinusitis and nasal polyps

3.2 Gastrointestinal

1.      Meconium ileus in neonates

2.      Pancreatic insufficiency

o    Steatorrhea

o    Fat-soluble vitamin deficiency (A, D, E, K)

3.      Failure to thrive

4.      Distal intestinal obstruction syndrome

5.      CF-related diabetes mellitus

6.      CF-related liver disease

3.3 Other Features

1.      Male infertility commonly due to congenital bilateral absence of the vas deferens

2.      Excess salt loss in sweat, which may cause dehydration and electrolyte abnormalities

4. Diagnosis

Diagnosis requires compatible clinical features or newborn screening findings plus evidence of CFTR dysfunction.

1.      Sweat chloride test

o    ≥60 mmol/L: consistent with CF

o    30 to 59 mmol/L: intermediate and requires further evaluation

o    ≤29 mmol/L: CF is unlikely, although rare exceptions occur

2.      Newborn screening

o    Elevated immunoreactive trypsinogen (IRT)

o    Screening alone does not establish the diagnosis

3.      Genetic testing

o    Identification of two CF-causing CFTR variants provides molecular evidence of CFTR dysfunction

o    Identification of only one CFTR variant does not exclude CF when other evidence of CFTR dysfunction is present

4.      Sputum culture

o    Identifies respiratory pathogens and guides antibiotic therapy

5.      Chest imaging

o    May show hyperinflation, bronchiectasis, mucus plugging, atelectasis, and scarring

6.      Pulmonary function tests

o    Typically show an obstructive pattern

5. Management

5.1 Airway Clearance

1.      Daily airway clearance therapy

2.      Inhaled hypertonic saline may be selectively offered based on individual clinical circumstances

3.      Dornase alfa may be selectively offered based on individual clinical circumstances

5.2 Pharmacologic Therapy

1.      Antibiotics guided by respiratory cultures and clinical infection

2.      Bronchodilators when clinically indicated, such as with bronchospasm or airway hyperreactivity

3.      CFTR modulator therapy is selected according to age, CFTR genotype, and regulatory eligibility

o    Ivacaftor for eligible responsive CFTR variants

o    Combination CFTR modulator therapies for eligible patients

o    Elexacaftor, tezacaftor, and ivacaftor is an important highly effective modulator combination for eligible patients

5.3 Nutritional Support

1.      Pancreatic enzyme replacement therapy for pancreatic insufficiency

2.      Fat-soluble vitamin supplementation (A, D, E, K) as indicated

3.      Individualized nutritional support, with increased caloric intake when needed for catch-up growth

5.4 Preventive Care

1.      Routine age-appropriate immunization, including annual influenza vaccination

2.      Regular monitoring of growth, nutritional status, respiratory microbiology, and lung function

5.5 Advanced Therapy

1.      Lung transplantation may be considered in advanced CF lung disease

6. Key Clinical Insight

In a child with characteristic clinical features, a sweat chloride concentration ≥60 mmol/L establishes the diagnosis of cystic fibrosis.

References

1.      Farrell PM, White TB, Ren CL, et al. Diagnosis of cystic fibrosis: consensus guidelines from the Cystic Fibrosis Foundation. J Pediatr. 2017;181S:S4-S15.e1. doi:10.1016/j.jpeds.2016.09.064.

2.      Lahiri T, Hempstead SE, Brady C, et al. Clinical practice guidelines from the Cystic Fibrosis Foundation for preschoolers with cystic fibrosis. Pediatrics. 2016;137(4):e20151784. doi:10.1542/peds.2015-1784.

3.      Mall MA, Burgel PR, Castellani C, et al. Cystic fibrosis. Nat Rev Dis Primers. 2024;10:53. doi:10.1038/s41572-024-00538-6.