Cystic Fibrosis

Cystic fibrosis is an autosomal recessive multisystem disorder caused by mutations in the CFTR gene. The gene encodes the cystic fibrosis transmembrane conductance regulator, a chloride channel protein essential for normal epithelial fluid and electrolyte transport.

The disorder produces thick, viscous secretions across multiple organ systems, most significantly the respiratory and pancreatic exocrine systems. It is the commonest life-limiting autosomal recessive condition in populations of predominantly Northern European ancestry.

Newborn screening is now widely implemented in many jurisdictions because early diagnosis and treatment bring substantial, well established benefit.

Highly effective CFTR-modulator disease-modifying therapy has transformed the prognosis and life expectancy for the substantial majority of affected individuals with an eligible genotype.

Pathophysiology and genetics

• Dysfunction of the CFTR chloride channel protein results from a broad range of mutations. They are classified into functional classes according to their effect on protein production, processing and function.
• The dysfunction produces abnormal epithelial ion and fluid transport. The result is thick, dehydrated mucous secretions that impair mucociliary clearance in the respiratory tract and obstruct pancreatic exocrine ducts.
• Sweat chloride concentration is abnormally elevated, which is the basis for the classic diagnostic sweat test.
• In the respiratory tract, impaired mucociliary clearance produces chronic mucus retention. This favours chronic bacterial colonisation and recurrent infection.
• Pseudomonas aeruginosa is a particularly important, characteristic pathogen, difficult to eradicate once chronic colonisation is established.
• A self-perpetuating cycle of infection, inflammation and progressive structural lung damage (bronchiectasis) follows. It ends in progressive respiratory failure, the principal cause of morbidity and mortality.
• Pancreatic exocrine insufficiency reflects obstruction of the pancreatic ducts by thick, inspissated secretions, with progressive pancreatic tissue destruction. It produces malabsorption of fat and fat-soluble vitamins.
• It occurs in the substantial majority (approximately 85 to 90 percent) of affected individuals. The degree of pancreatic involvement correlates with the CFTR mutation class present.
• The specific CFTR mutation determines eligibility for CFTR-modulator therapy. Different modulator agents target the molecular defect of particular mutation classes, a paradigm example of genotype-directed, precision medicine.

• Meconium ileus is a form of neonatal bowel obstruction caused by abnormally thick, inspissated meconium. It occurs in a meaningful proportion of affected infants and is an important, characteristic early presentation. It is sometimes the first clue prompting evaluation for cystic fibrosis in an infant not identified through newborn screening.
• Recurrent or persistent respiratory symptoms are the dominant respiratory manifestation: chronic productive cough, recurrent lower respiratory tract infection and, over time, progressive bronchiectasis with chronic sputum production.
• Chronic bacterial colonisation drives progressive, cumulative structural lung damage. It follows a characteristic sequence, commonly beginning with Staphylococcus aureus and Haemophilus influenzae in early childhood. A substantial proportion of patients progress to chronic Pseudomonas aeruginosa colonisation as the disease advances.
• Pancreatic exocrine insufficiency produces malabsorption. Features are steatorrhoea (bulky, oily, foul-smelling stools), faltering growth and weight gain despite adequate or even increased caloric intake, and fat-soluble vitamin deficiency (vitamins A, D, E, and K). It needs specific, proactive management.
• Cystic fibrosis related diabetes reflects progressive pancreatic endocrine as well as exocrine dysfunction. It is an increasingly recognised complication, typically developing in later childhood and adolescence.
• It has a distinct pathophysiology and management approach compared with type 1 or type 2 diabetes, and warrants structured screening from a defined age.
• Male infertility, resulting from congenital bilateral absence of the vas deferens, occurs in the great majority of affected men. It is generally non-life-threatening but relevant to reproductive counselling.
• Female fertility may be reduced but is generally preserved to a greater degree. Pregnancy with significant lung disease requires specialist, multidisciplinary management because of the physiological demands pregnancy places on respiratory function.
• Additional manifestations: nasal polyposis and chronic sinusitis, cystic fibrosis-related liver disease, and reduced bone mineral density.
• Distal intestinal obstruction syndrome is a cystic fibrosis-specific form of bowel obstruction beyond infancy. It relates to the same abnormal intestinal secretions responsible for neonatal meconium ileus.
• Together these reflect the multisystem nature of the condition.

• Newborn screening is the primary diagnostic pathway in the great majority of contemporary healthcare settings with established screening programmes. It measures immunoreactive trypsinogen on the routine newborn dried blood spot sample. Genetic testing for common CFTR mutations typically follows where the initial result is elevated.
• Screening allows early diagnosis and treatment initiation before significant symptoms or complications.
• The sweat chloride test is the definitive, gold-standard test. It measures chloride concentration in sweat obtained through pilocarpine iontophoresis. An elevated concentration (generally above 60 mmol per litre) confirms the diagnosis.
• Levels in an intermediate range warrant more detailed genetic evaluation, because of the possibility of a milder, atypical phenotype.
• CFTR genetic testing identifies the mutations present on each allele. It provides a definitive molecular diagnosis and directly informs eligibility for genotype-targeted CFTR-modulator therapies. It is an essential, standard part of diagnostic evaluation.
• Where diagnosis is not established through newborn screening, a compatible clinical pattern of recurrent respiratory infection, faltering growth or malabsorption should prompt evaluation including sweat chloride testing. This applies to an infant born before screening implementation or, less commonly, a false negative screening result.

• CFTR-modulator therapy is a transformative, disease-modifying advance. Agents include ivacaftor, lumacaftor-ivacaftor, tezacaftor-ivacaftor and elexacaftor-tezacaftor-ivacaftor. Each targets the underlying molecular defect according to the CFTR mutation class present.
• Elexacaftor-tezacaftor-ivacaftor is the most broadly effective and widely applicable current combination. It is eligible for, and gives substantial benefit in, the great majority of patients with at least one copy of the commonest CFTR mutation (F508del).
• It produces substantial improvement in lung function, marked reduction in pulmonary exacerbation frequency, and improved nutritional status. It has transformed the prognosis and life expectancy for the substantial majority of eligible patients.
• Airway clearance therapy is an essential, foundational part of respiratory management. It comprises regular, structured chest physiotherapy to mobilise and clear retained secretions, together with inhaled mucolytic agents (including dornase alfa and hypertonic saline).
• Perform airway clearance daily regardless of current symptoms, because it slows the progressive accumulation of structural lung damage.
• Treat pulmonary exacerbations promptly and aggressively, with intensified airway clearance and appropriate antibiotic therapy. Guide antibiotics by regular respiratory tract culture surveillance and the pattern of chronic colonisation in the individual patient.
• Individualise antibiotic regimen and route (oral, inhaled, or intravenous) to exacerbation severity and organism profile. Intravenous therapy generally requires hospital admission or, in some circumstances, structured home intravenous therapy.
• Chronic suppressive inhaled antibiotic therapy (typically inhaled tobramycin or colistin) is a standard component of management in patients with established chronic Pseudomonas aeruginosa colonisation. It aims to reduce bacterial burden and exacerbation frequency.
• Pancreatic enzyme replacement therapy, taken with every meal and snack, is essential, standard treatment for the substantial majority of patients with pancreatic exocrine insufficiency.
• Add fat-soluble vitamin supplementation and structured nutritional support, because nutritional status is directly relevant to outcome and prognosis. A high-calorie, high-fat diet is generally recommended to compensate for malabsorption.
• Screen regularly for specific complications, including annual oral glucose tolerance testing for cystic fibrosis-related diabetes from a defined age. Monitor bone density, liver function and nutritional status.
• Care is lifelong and delivered through specialist, multidisciplinary cystic fibrosis centres.
• Lung transplantation is an option for advanced, end-stage respiratory disease not adequately managed with medical measures. CFTR-modulator therapy has meaningfully reduced the proportion of patients progressing to this stage.
• Provide psychosocial support for the burden of a demanding, lifelong daily treatment regimen and for educational, occupational and family life considerations.
• Provide genetic counselling on the autosomal recessive inheritance pattern and recurrence risk for future pregnancies, and plan structured transition from paediatric to adult cystic fibrosis services.
• The overall prognosis for children diagnosed today, particularly those eligible for CFTR-modulator therapy, is now substantially more favourable than at any previous point in the management of this disease.