Cystic Fibrosis in Children

1. Define cystic fibrosis (CF) and its genetic basis:

Definition: An autosomal recessive multisystem disease caused by mutations in the CFTR gene (Cystic Fibrosis Transmembrane Conductance Regulator). The most common mutation is F508del.
Mechanism: The defect in the chloride channel leads to impaired transport of chloride and water across cell membranes, resulting in abnormally viscous (thick) secretions in exocrine and certain endocrine glands.

Incidence: In the Czech Republic, approximately 1 in 2,500–3,000 newborns.
Carrier frequency: Approximately 1 in 25 individuals in the Central European population are carriers.
Screening: Newborn screening for CF has been mandatory in the Czech Republic since 2009.

CFTR dysfunction $\rightarrow$ decreased chloride transport -> secondary increase in sodium and water reabsorption -> dehydrated, viscid mucus obstruction of ducts/lumens (lungs, pancreas, bile ducts) -> chronic inflammation and tissue damage.
Sweat Glands: In sweat ducts, CFTR normally reabsorbs chloride; its failure leads to high salt concentration in sweat ("salty sweat").

Primary test: Measurement of Immunoreactive Trypsinogen (IRT) from a dried blood spot (Guthrie card).
Follow-up: If IRT is elevated, the next steps include genetic testing (for common mutations) and the sweat test.
Caveat: Screening can be falsely negative; clinical suspicion always warrants diagnostic testing regardless of screening results.

The severity of the phenotype depends on the combination of both alleles (genotype).
Severe (Class I–III) mutations: Often associated with early-onset pancreatic insufficiency and severe respiratory involvement.
Mild (Class IV–VI) mutations: May result in pancreatic sufficiency, recurrent acute pancreatitis later in life, or milder pulmonary disease.

Respiratory: Chronic productive cough, recurrent bronchitis/pneumonia, bronchiectasis, nasal polyps, and digital clubbing.
Gastrointestinal: Exocrine pancreatic insufficiency (steatorrhea, malabsorption, failure to thrive), distal intestinal obstruction syndrome (DIOS), meconium ileus, and CF-related liver disease (cirrhosis).
Metabolic: Risk of hyponatremic, hypochloremic metabolic alkalosis (especially during heat/sweating).
Endocrine: CF-Related Diabetes (CFRD).
Reproductive: Males: Congenital Bilateral Absence of the Vas Deferens (CBAVD) leading to azoospermia; Females: reduced fertility due to thick cervical mucus.

Newborns: Meconium ileus (bowel obstruction), delayed passage of meconium, metabolic alkalosis.
Infants/Toddlers: Failure to thrive, bulky/oily stools (steatorrhea), rectal prolapse, recurrent respiratory infections.
School Age: Chronic sinusitis, persistent cough, growth retardation.
Adolescents/Adults: Declining lung function (FEV1), CFRD, infertility, and psychosocial challenges.

Sweat Test (Pilocarpine Iontophoresis): The gold standard.
- Positive: Chloride > 60 mmol/l.
- Borderline: 30–60 mmol/l.
- Negative: < 30 mmol/l.
Diagnostic Confirmation: Requires clinical symptoms (or positive screening) PLUS evidence of CFTR dysfunction (two positive sweat tests OR identification of two disease-causing mutations).

Respiratory Therapy: Daily airway clearance (physiotherapy), inhalation of hypertonic saline, and Dornase alfa (Pulmozyme) to thin mucus.
Antibiotic Therapy: Eradication of initial pathogens and aggressive treatment of pulmonary exacerbations (I.V. or inhaled).
Nutritional Support: High-calorie diet, Pancreatic Enzyme Replacement Therapy (PERT) with every meal, fat-soluble vitamin supplementation (A, D, E, K), and increased salt intake.

High-risk: Pseudomonas aeruginosa and Burkholderia cepacia complex. These significantly accelerate lung function decline.
Others: S. aureus, H. influenzae, Nontuberculous Mycobacteria (NTM), and Aspergillus.
Prevention: Strict patient isolation (patients with CF must never meet in person) and rigorous hygiene to prevent cross-contamination.

Modern drugs (e.g., Ivacaftor, Tezacaftor, Elexaftor) act as potentiators or correctors that improve the function of the defective CFTR protein.
This "causal" therapy significantly improves lung function, BMI, and overall life expectancy, but is only effective for specific mutations.

Historically, CF was a fatal childhood disease (median survival < 10 years in the 1960s). Current median survival is 40–50+ years.
Lung disease remains the primary cause of mortality; end-stage disease may require lung transplantation.

Explain that a positive screening is not a final diagnosis but a reason for urgent further testing.
If confirmed, introduce the multidisciplinary CF team (pulmonologist, nutritionist, physiotherapist) and emphasize that with modern treatment, many children live full, active lives.