Cystic Fibrosis

Classic Cystic Fibrosis (Typical CF)

• Defined by clinical manifestations in at least one organ system (commonly respiratory or gastrointestinal) and evidence of CFTR dysfunction.
• Diagnostic criteria include:
  • A sweat chloride concentration ≥60 mmol/L on two occasions, or
  • Identification of two CF-causing mutations on separate alleles, or
  • Demonstrated CFTR dysfunction via abnormal nasal potential difference or intestinal current measurement.
• Typical features include chronic pulmonary disease, pancreatic insufficiency, male infertility (often due to congenital bilateral absence of the vas deferens), and elevated sweat chloride levels.

Non-Classic Presentations (Previously "Atypical CF")

• Refers to individuals who meet CF diagnostic criteria but lack one or more hallmark features of classic CF.
• These patients may have milder or monosystemic involvement and may present later in life, often with normal or borderline sweat chloride values (30–59 mmol/L).
• Genetic testing typically reveals uncommon or less deleterious CFTR mutations.
• Diagnosis is based on presence of clinical features with confirmation of CFTR dysfunction (e.g., abnormal nasal potential difference or two disease-causing CFTR mutations in trans).
• The terms “non-classic” or “atypical” are discouraged in favour of more precise phenotypic or genetic descriptors.

CFTR-Related Disorder

• This term encompasses conditions associated with CFTR dysfunction that do not meet full diagnostic criteria for CF.
• Involvement is typically limited to a single organ system and includes conditions such as:
  • Isolated obstructive azoospermia (congenital bilateral absence of the vas deferens),
  • Idiopathic chronic pancreatitis,
  • Chronic sinusitis,
  • Isolated bronchiectasis.
• Diagnostic features include intermediate sweat chloride levels or the presence of only one CFTR mutation.
• Comprehensive CFTR gene analysis (including sequencing and testing for large rearrangements) is necessary to confirm that the individual does not have two disease-causing mutations. If two are found, the diagnosis should be revised to CF.

CFTR-Related Metabolic Syndrome (CRMS)/CF Screen Positive Inconclusive Diagnosis (CFSPID)

• Designation used for infants with a positive newborn screening result but inconclusive diagnostic testing.
• Typical findings include:
  • Sweat chloride <30 mmol/L with two CFTR mutations, at least one of which is of uncertain or mild clinical significance, or
  • Sweat chloride between 30–59 mmol/L with zero or one CF-causing mutation.
• Although not diagnosed with CF, these children require careful long-term follow-up, as some may eventually meet diagnostic criteria for CF with time.

Genetic Basis and Inheritance

• Cystic fibrosis (CF) is an autosomal recessive disorder caused by pathogenic variants in the CFTR (cystic fibrosis transmembrane conductance regulator) gene, located on chromosome 7q31.
• The CFTR gene encodes a protein that functions as a chloride and bicarbonate channel on the apical membrane of epithelial cells in organs such as the lungs, pancreas, gastrointestinal tract, sweat glands, and reproductive system.
• Both alleles of the CFTR gene must carry disease-causing mutations for clinical disease to manifest. Heterozygous carriers typically remain asymptomatic.

Mutation Spectrum

• Over 2000 different mutations in the CFTR gene have been identified. These mutations are grouped into six functional classes based on the nature of the defect:
  • Class I: Defective protein synthesis (e.g., G542X)
  • Class II: Defective protein processing/trafficking (e.g., F508del)
  • Class III: Defective regulation (e.g., G551D)
  • Class IV: Defective chloride conductance (e.g., R347P)
  • Class V: Reduced protein production (e.g., A455E)
  • Class VI: Decreased protein stability at the cell surface (e.g., 120del123)

Prevalent Mutations

• The most common mutation worldwide is F508del (a class II mutation), found in approximately 80–90% of individuals with CF in Northern Europe, with ~50% of those being homozygous.
• Other population-specific mutations include:
  • W1282X and Δ1152H in Ashkenazi Jews
  • A455E in the Dutch and northern Quebec populations
  • Δ1152H accounts for 5.2% of CFTR mutations in Jewish cohorts

Genotype–Phenotype Correlation

• Homozygosity for F508del is strongly associated with pancreatic exocrine insufficiency and increased risk of meconium ileus.
• Milder mutations (e.g., R117H) often correlate with preserved pancreatic function and later disease onset.
• However, genotype alone does not always predict phenotype due to the influence of environmental factors and genetic modifiers.

Modifier Genes and Environmental Factors

• The variability in disease severity among patients with identical CFTR mutations underscores the role of modifier genes and environmental interactions.
• Modifier genes implicated include:
  • KITL: Influences mast cell differentiation; its reduced expression affects immune responses
  • ICAM-1 and selectins: Mediate neutrophil trafficking and inflammation
  • MCLCA3 (murine) and HCLCA1 (human): Regulate mucus production via goblet cells; their downregulation is linked to increased disease severity
• Murine models with altered expression of these genes have demonstrated that correcting such modifiers can improve survival and intestinal health.
• Environmental contributors include diet, infections, and therapeutic interventions such as pancreatic enzyme replacement, which in neonates may induce bowel strictures contributing to intestinal obstruction.

Pathophysiological Consequences

• CFTR dysfunction leads to impaired chloride and bicarbonate transport, disrupting fluid secretion and resulting in dehydrated, viscous secretions.
• These thick secretions affect multiple organ systems, leading to recurrent infections, pancreatic insufficiency, gastrointestinal complications, and infertility
• Inflammatory responses are exaggerated in CF, with neutrophils and mast cells releasing cytokines and proteases that worsen tissue damage and mucus accumulation.

Molecular and Cellular Basis

• Cystic fibrosis results from pathogenic mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene, which encodes a cAMP-regulated chloride and bicarbonate ion channel located in the apical membrane of epithelial cells.
• CFTR dysfunction alters epithelial ion transport, leading to decreased chloride secretion, increased sodium reabsorption, and water retention within cells. This results in dehydrated, hyperviscous secretions across mucosal surfaces.

Functional Classification of CFTR Mutations

• Class I: Defective protein synthesis due to premature stop codons or splicing errors; complete absence of CFTR protein.
• Class II: Defective protein processing and trafficking (e.g. F508del); protein degraded before reaching the membrane.
• Class III: Defective regulation; CFTR reaches the membrane but is non-functional (e.g. G551D).
• Class IV: Reduced chloride conductance due to altered channel structure.
• Class V: Reduced synthesis of CFTR protein due to unstable mRNA or decreased protein stability.
• Class VI: Accelerated turnover of CFTR protein from the cell surface (less commonly classified).

Airway and Pulmonary Pathophysiology

• Thickened mucus and defective mucociliary clearance result in mucus plugging and airway obstruction.
• Early bacterial colonisation (notably Pseudomonas aeruginosa) triggers a sustained neutrophilic inflammatory response.
• Neutrophil elastase degrades host defence molecules (e.g., IgG, complement receptors), promotes IL-8 secretion, and causes further tissue damage.
• Chronic cycles of infection and inflammation lead to bronchiectasis, hypoxaemia, and ultimately respiratory failure—the leading cause of death in CF.
• Exposure to environmental factors such as secondhand smoke exacerbates lung damage, particularly in individuals with modifier variants like TGFβ1.

Sinus Involvement

• Impaired chloride secretion and increased sodium absorption desiccate sinus mucus, impairing clearance.
• This is compounded by ciliary dysfunction and bacterial colonisation, leading to chronic sinusitis and nasal polyposis.

Pancreatic Pathophysiology

• Pancreatic ductal obstruction by inspissated secretions prevents enzyme delivery to the duodenum.
• Malabsorption of fats and fat-soluble vitamins (A, D, E, K) ensues, contributing to failure to thrive and steatorrhoea.
• Progressive destruction of pancreatic acini may lead to chronic pancreatitis and, in severe cases, secondary diabetes mellitus due to islet cell destruction.

Hepatobiliary Manifestations

• CFTR dysfunction in biliary epithelial cells results in bile duct plugging, cholestasis, and ultimately focal or multilobular cirrhosis.
• Gallstones occur in up to 15% of patients, independent of pancreatic status, due to altered bile acid composition and gallbladder dysmotility.
• Liver disease may be compounded by malnutrition or right heart failure-induced hepatic congestion.

Intestinal Pathophysiology

• Neonatal meconium ileus is associated with dehydrated, protein-rich intestinal contents due to reduced intraluminal water and defective mucus secretion.
• Obstruction may also arise from distal intestinal obstruction syndrome (DIOS), strictures, intussusception, or adhesions.
• Impaired motility and scarring contribute to ongoing gastrointestinal symptoms.

Meconium Ileus

• Associated with increased albumin and reduced carbohydrate content in intestinal secretions.
• Murine CF models suggest that meconium ileus can occur despite preserved pancreatic function, implicating intrinsic intestinal defects and dysmotility.

Sweat Gland Pathophysiology

• In contrast to other tissues, CFTR in sweat glands functions to reabsorb chloride from sweat; its dysfunction leads to sodium and chloride loss onto the skin.
• The resultant high salt content is the basis of the diagnostic sweat test and may predispose to hyponatraemic dehydration.

Urogenital Involvement

• Congenital bilateral absence of the vas deferens is the most common cause of infertility in males with CF.
• Females may experience reduced fertility due to viscous cervical mucus and complications related to malnutrition or chronic illness.

Expanded Role of CFTR

• CFTR interacts with multiple cellular proteins through its PDZ-binding domain, linking it to cytoskeletal elements, kinases, phosphatases, and other ion channels.
• These interactions influence cellular signalling, maturation, and inflammatory responses, contributing to phenotypic heterogeneity.
• Modifier genes and non-CFTR pathways (e.g., KITL, MCLCA3, ICAM-1) influence disease severity and organ-specific manifestations.

Global and Regional Prevalence

• Cystic fibrosis (CF) affects over 100,000 individuals globally.
• In the UK, approximately 10,900 people live with CF, while in the United States the number is around 32,000.
• The incidence varies widely by ethnicity:
  • White (Northern European descent): 1 in 3000–3500 live births in the US; as frequent as 1 in 377 in parts of England.
  • Hispanic Americans: 1 in 9200–10,000
  • Native Americans: 1 in 10,500
  • Black Americans: 1 in 15,000–17,000
  • Asian Americans: 1 in 30,000–31,000
  • Native Asians and Africans: <1 in 90,000 live births, with increased prevalence in diaspora populations due to admixture.

Carrier Frequency

• In people of Northern European descent, the carrier rate of CFTR mutations is up to 1 in 20.
• As CF is inherited in an autosomal recessive pattern, each child of two heterozygous carriers has a 25% risk of inheriting the disease.

Mutation Distribution

• The ΔF508 mutation is the most common CFTR variant and is predominantly seen in individuals of European ancestry.
• While genotype prevalence differs among ethnic groups, clinical expression is largely similar across races. However, Black patients have been observed to have earlier diagnosis, poorer nutrition, and lower pulmonary function, possibly influenced by socioeconomic disparities rather than biological factors.

Trends in Incidence

• Newborn screening and population-based carrier screening have led to a reduction in CF incidence in many high-income countries.
  • In the US, 1017 new cases were reported in 2006, compared to 779 in 2021.
  • The proportion of diagnoses via newborn screening rose from 21.2% to 64.4% during the same period.
• Mild and monosystemic presentations, often with atypical genotypes, are increasingly recognised due to improved diagnostics and awareness.

Age Distribution and Survival

• CF was historically considered a childhood disease; however, survival improvements have resulted in a growing adult population.
  • Median age at death in the US was 33.9 years as of 2021.
  • Life expectancy for those born between 2018–2022 is projected to reach 56 years.
• The shift towards adult prevalence is primarily due to advances in treatment, including nutritional support, antimicrobial therapy, and CFTR modulators.

Mortality and Post-Transplant Outcomes

• Progressive pulmonary disease remains the leading cause of death in CF.
• Lung transplantation may be pursued in advanced cases:
  • Post-transplant survival rates in the US: 85.3% at 1 year, 67% at 3 years, and 54.3% at 5 years.

Sex-Based Differences

• Females with CF experience more rapid decline in lung function and earlier death compared to males.
• Hormonal influences, particularly during puberty, are hypothesised to modulate immune and mucosal defences, exacerbating disease progression.

Microbial Colonisation

• Pseudomonas aeruginosa remains the most prevalent and persistent respiratory pathogen in CF:
  • Prevalence: ~29.8% in European CF populations and 49.6% in US CF populations.
  • Over 60% of adults with CF are colonised.
  • Aggressive eradication protocols have modestly reduced prevalence in recent years.

Perinatal and Neonatal History

• Delayed passage of meconium: Occurs in 10–20% of newborns with CF and may present as meconium ileus, occasionally complicated by bowel perforation and meconium peritonitis.
• Prolonged neonatal jaundice or unexplained cholestasis: May signal early hepatic involvement.
• Prenatal findings: Hyperechogenic bowel, bowel dilatation, or absent gallbladder on ultrasound may raise suspicion; family history warrants prenatal CF carrier screening.
• Newborn screening: A positive result typically includes elevated immunoreactive trypsinogen (IRT), often followed by DNA testing for CFTR mutations or confirmatory sweat testing.

Growth and Nutritional Concerns

• Failure to thrive: Poor weight gain despite normal or increased appetite is a classic early manifestation, especially in infants with untreated pancreatic insufficiency.
• Voracious appetite: Suggestive of compensatory intake due to malabsorption.
• Signs of malnutrition: Including oedema, alopecia, dermatitis, and hypoproteinaemia in infants.

Respiratory History

• Chronic or wet-sounding cough: Recurrent lower respiratory tract infections (bronchitis, pneumonia), especially requiring antibiotics, should prompt evaluation.
• Recurrent sinopulmonary infections: Sinusitis, bronchitis, persistent rhinitis, and nasal congestion.
• Haemoptysis: Often associated with advanced lung disease.
• History of asthma or wheeze: May suggest coexisting allergic bronchopulmonary aspergillosis or atypical CF presentation.
• Prolonged “colds” or “chestiness” in infancy or early childhood.

Gastrointestinal Symptoms

• Bulky, greasy, foul-smelling stools (steatorrhoea): Indicative of fat malabsorption from pancreatic insufficiency.
• Recurrent or chronic abdominal pain: May suggest distal intestinal obstruction syndrome (DIOS), intussusception, or pancreatitis.
• Constipation or rectal prolapse: Seen in young children due to untreated pancreatic insufficiency or DIOS.
• History of acute appendicitis: Although common in the general population, may mimic or mask DIOS in CF patients.

Pancreatic and Hepatic Manifestations

• History of pancreatitis: Especially in patients who retain pancreatic sufficiency; presents with abdominal pain, nausea, vomiting, and elevated amylase/lipase.
• Symptoms of fat-soluble vitamin deficiency: Such as night blindness (vitamin A), rickets (vitamin D), easy bruising (vitamin K), or neuropathy (vitamin E).
• Symptoms of liver disease: May include right upper quadrant pain, hepatosplenomegaly, variceal bleeding, or jaundice.
• History of gallstones: Right upper quadrant discomfort or biliary colic in a young person may be a clue.

Reproductive History

• Infertility in males: Strong historical clue. Most men with CF are infertile due to congenital bilateral absence of the vas deferens (CBAVD), although spermatogenesis remains intact.
• Reduced fertility in females: Due to tenacious cervical mucus and/or malnutrition; increased fertility has been observed with CFTR modulator therapy.

ENT and Sinus Symptoms

• Chronic rhinosinusitis or nasal polyps: Persistent nasal congestion, postnasal drip, hyposmia/anosmia, snoring, or obstructive sleep apnoea.
• Recurrent otitis media: Particularly in infancy.

Musculoskeletal and Dermatological Clues

• Delayed puberty or decreased growth velocity: Can reflect nutritional deficiencies or chronic inflammation.
• Digital clubbing: May be noted historically by caregivers or observed in old photos.
• A history of aquagenic wrinkling: Wrinkling of the palms within minutes of water exposure is highly suggestive.
• Scaly dermatitis or acrodermatitis enteropathica: Reflects zinc or essential fatty acid deficiency.

Renal and Electrolyte Abnormalities

• History of dehydration episodes: Especially in infants or during hot weather, often associated with hyponatraemia, hypokalaemia, and metabolic alkalosis (pseudo-Bartter syndrome).
• Nephrolithiasis or nephrocalcinosis: Especially in adolescents or adults, may indicate fat malabsorption-related enteric hyperoxaluria.

Haematologic and Cardiovascular Clues

• Unexplained anaemia: Due to malabsorption, chronic inflammation, or blood loss.
• Episodes of venous thrombosis: Particularly if associated with central venous catheter use.
• History of cardiovascular events: Although rare in young patients, individuals with CF are increasingly surviving into adulthood and may develop typical cardiovascular disease.

Family and Ethnic Background

• Positive family history: Especially of unexplained early respiratory disease or sibling death in infancy.
• Known parental carrier status: Strong predictor, with a 25% recurrence risk in each pregnancy.
• Ethnic background: CF is most common among those of European descent, though underdiagnosis in non-white populations is possible.

Adult Presentation Patterns

• Later diagnosis: May occur in milder or monosystemic forms (e.g., isolated male infertility, chronic sinusitis, or pancreatitis).
• Milder gastrointestinal or pulmonary symptoms: May not fulfil classic diagnostic criteria.
• Equivocal sweat chloride tests: Often found in adults with atypical CF or CFTR-related disorders.

General Appearance and Growth

• Failure to thrive: Children may appear thin or undernourished despite an appropriate or increased appetite.
• Short stature or delayed growth: Often secondary to malabsorption, chronic inflammation, or endocrinopathies.
• Signs of malnutrition:
  • Oedema due to hypoproteinaemia.
  • Dry, scaly skin (vitamin A or essential fatty acid deficiency).
  • Cheilosis or angular stomatitis (vitamin B deficiency).
  • Alopecia, dermatitis, and acrodermatitis enteropathica (zinc deficiency).

Respiratory System

• Tachypnoea and increased work of breathing: Subcostal/intercostal retractions in infants or young children.
• Productive or wet-sounding cough: Often described as harsh or persistent.
• Wheezing or crackles:
  • Crackles are common with bronchiectasis or pneumonia.
  • Wheezing may indicate airway obstruction, often exacerbated in cases with allergic bronchopulmonary aspergillosis (ABPA).
• Increased anteroposterior (AP) chest diameter: Sign of air trapping or hyperinflation.
• Hyperresonance on percussion: Suggests lung hyperinflation or bronchiectasis.
• Cyanosis: Perioral or peripheral, in advanced pulmonary disease.
• Digital clubbing: Enlargement of the distal phalanges with loss of nail bed angle, common in moderate to advanced lung disease.
• Nasal polyps: Visible on anterior rhinoscopy; commonly associated with chronic sinusitis.
• Panopacification of the sinuses: Noted on radiographic imaging; may be suspected clinically in those with persistent nasal congestion or facial pressure.

Gastrointestinal and Hepatobiliary System

• Abdominal distension: Due to gas, obstruction, or hepatosplenomegaly.
• Palpable liver or spleen:
  • Hepatomegaly from focal biliary cirrhosis or hepatic steatosis.
  • Splenomegaly from portal hypertension or hypersplenism.
• Meconium ileus signs in neonates:
  • Dilated, doughy bowel loops with palpable masses.
  • Narrow anal canal on digital rectal examination.
• Rectal prolapse: Occasional finding in younger children, especially before enzyme therapy.
• Signs of vitamin deficiency:
  • Rickets (rachitic rosary, bowing of long bones) in vitamin D deficiency.
  • Easy bruising or prolonged bleeding (vitamin K deficiency).
  • Night blindness (vitamin A deficiency).

Genitourinary Findings

• Males: Bilateral absence of the vas deferens (CBAVD), often presenting as an empty scrotum or absent vas deferens on examination.
• Females: No specific exam findings, but history may suggest subfertility.

Dermatological Clues

• Aquagenic wrinkling of the palms (AWP):
  • Occurs within 3–7 minutes of water exposure.
  • Highly suggestive of CF, especially in children or adolescents.
• Dermatitis and periorificial lesions: May suggest malabsorption-related nutrient deficiencies.

Musculoskeletal System

• Scoliosis or kyphosis: More common in older children and adolescents.
• Hypertrophic osteoarthropathy:
  • Swelling and tenderness over distal long bones.
  • Associated with advanced pulmonary disease and chronic hypoxia.

Complications Detectable on Examination

• Pulmonary hypertension and cor pulmonale:
  • Jugular venous distension, right ventricular heave, loud P2 component of the second heart sound.
• Pneumothorax:
  • Decreased breath sounds and hyperresonance on the affected side.
• Hepatic decompensation:
  • Ascites, spider naevi, palmar erythema, or a firm, nodular liver edge.

Atypical or Isolated Findings

• CBAVD in otherwise healthy adult males may be the only clue to CF.
• Polyuria and polydipsia in infants may mimic diabetes insipidus but represent CF-related diabetes or salt-wasting.
• Nephrolithiasis/nephrocalcinosis:
  • May present with flank tenderness or haematuria.
  • Not always apparent on physical exam but important in long-term monitoring.

Sweat Chloride Testing

• The sweat chloride test via pilocarpine iontophoresis is the gold standard for initial diagnosis.
• Positive result (≥60 mmol/L): Strongly suggests cystic fibrosis and should be confirmed by repeating the test.
• Intermediate result (30–59 mmol/L): Requires repeat sweat testing and CFTR genetic analysis.
• Negative result (<30 mmol/L): CF is unlikely, though rare genotypes may still be associated with CF. In cases of strong clinical suspicion, further evaluation is warranted.
• Sweat testing is valid at any age, though younger infants may not produce adequate sweat volume for reliable results. Retesting is advised if sweat volume is insufficient.
• Conditions such as malnutrition, adrenal insufficiency, or improper technique may yield false results.

Genetic Testing

• Initial screening: Focuses on the most common CFTR mutations using mutation panels.
• Extended analysis: Performed if only one or no mutations are identified or if sweat test results are borderline. This may include full CFTR sequencing and testing for deletions or duplications.
• Two disease-causing mutations on separate alleles confirm the diagnosis of CF.
• Identification of variants of unclear significance or only one mutation may lead to a diagnosis of CFTR-related metabolic syndrome (CRMS) or CF screen-positive, inconclusive diagnosis (CFSPID).
• Genetic screening is particularly important in multiethnic populations due to mutation variability.

Nasal Potential Difference (NPD)

• Measures transepithelial voltage across the nasal mucosa to assess CFTR function.
• Used in cases with inconclusive sweat/genetic testing.
• Typical CF pattern: elevated baseline potential, pronounced response to amiloride, minimal response to chloride-free solution with isoproterenol.
• Requires specialised equipment and personnel; not widely available.

Newborn Screening

• Universal in many countries, uses immunoreactive trypsinogen (IRT) as the initial marker.
• Elevated IRT prompts second-tier testing (repeat IRT, DNA analysis, or both).
• Infants with elevated IRT but inconclusive genetic findings are followed as potential CFSPID.
• Positive newborn screens necessitate confirmatory sweat testing from age two weeks onwards (if weight >2 kg).

Imaging Studies

• Chest radiography: May show peribronchial thickening, hyperinflation, infiltrates, and bronchiectasis.
• Sinus CT: Often reveals pansinusitis and may support diagnosis in appropriate clinical context.
• Abdominal radiography: Helpful in suspected meconium ileus; characteristic “soap-bubble” sign may be present.
• Prenatal ultrasound: Hyperechogenic bowel, bowel dilatation, or absent gallbladder raises suspicion in high-risk pregnancies.

Microbiological Testing

• Sputum cultures and deep throat swabs: Detect pathogens such as Pseudomonas aeruginosa, Staphylococcus aureus, and Burkholderia cepacia.
• Bronchoalveolar lavage may be used in young or non-expectorating children.

Pancreatic Function Testing

• Fecal elastase: Common, non-invasive screening for exocrine pancreatic insufficiency.
• 72-hour fecal fat collection: Assesses fat malabsorption but is cumbersome.
• Direct stimulation tests with secretin are rarely used due to invasiveness.

Additional Laboratory Tests

• Immunoreactive trypsinogen (IRT): Used primarily in newborn screening; elevated in most infants with CF.
• Blood tests: May reveal electrolyte imbalances (e.g., hyponatraemia, hypochloraemia), especially during heat exposure or illness.
• Semen analysis and testicular examination in males with suspected infertility may reveal azoospermia and congenital absence of the vas deferens.

Pulmonary Function Testing

• In children over age five, spirometry is standard.
• FEV1 decline is the most used parameter to track disease progression.
• In infants and younger children, impulse oscillometry or lung clearance index (LCI) may detect early airway changes.

Advanced Imaging

• High-resolution CT: More sensitive than spirometry in detecting early bronchiectasis.
• Hyperpolarised gas MRI: Detects ventilation heterogeneity; useful in early lung disease, though primarily a research tool.

Contrast Enema

• Diagnostic and therapeutic in cases of suspected meconium ileus.
• Reveals a narrow (unused) colon and can show reflux of contrast into dilated loops of small intestine.

Primary Ciliary Dyskinesia (PCD)

• Clinical Features:
  • Recurrent sinopulmonary infections
  • Chronic otitis media
  • Nasal congestion and sinusitis
  • Male infertility
  • Situs inversus in ~50% of cases (Kartagener’s syndrome)
• Distinguishing Points:
  • Not associated with pancreatic insufficiency
  • May present with neonatal respiratory distress
• Investigations:
  • Low nasal nitric oxide levels
  • Ciliary ultrastructure on electron microscopy or high-speed videomicroscopy
  • Genetic testing for mutations in dynein arm–related genes

Primary Immunodeficiency

• Clinical Features:
  • Recurrent bacterial infections, often involving the respiratory tract
  • May involve other organ systems (e.g., skin, GI tract)
  • May be associated with growth failure or autoimmune features
• Distinguishing Points:
  • Not typically associated with malabsorption or pancreatic insufficiency
  • Broader infection spectrum (e.g., fungal, viral)
• Investigations:
  • Quantitative immunoglobulin levels (IgG, IgA, IgM, IgE)
  • Lymphocyte subset analysis and functional immune testing

Asthma

• Clinical Features:
  • Episodic wheeze, cough, and dyspnoea
  • Atopic history
• Distinguishing Points:
  • Absence of digital clubbing or chronic purulent sputum
  • Usually responsive to bronchodilators and inhaled corticosteroids
• Investigations:
  • Spirometry with bronchodilator reversibility
  • No definitive diagnostic test; diagnosis is clinical

Chronic Aspiration and Gastro-Oesophageal Reflux Disease (GORD)

• Clinical Features:
  • Cough, recurrent pneumonias, feeding difficulties
  • Poor weight gain
• Distinguishing Points:
  • Typically no evidence of pancreatic insufficiency
  • Can coexist with CF
• Investigations:
  • Modified barium swallow
  • 24-hour pH impedance monitoring

Coeliac Disease

• Clinical Features:
  • Diarrhoea, abdominal bloating, failure to thrive
  • Iron-deficiency anaemia, dermatitis herpetiformis
• Distinguishing Points:
  • Symptoms resolve with gluten-free diet
  • No recurrent chest infections or pancreatic insufficiency
• Investigations:
  • Tissue transglutaminase (tTG-IgA) antibodies
  • Small bowel biopsy confirming villous atrophy

Protein-Losing Enteropathy

• Clinical Features:
  • Generalised oedema, diarrhoea, failure to thrive
• Distinguishing Points:
  • Can be associated with lymphatic anomalies or congenital heart disease (e.g., post-Fontan)
• Investigations:
  • Faecal α1-antitrypsin clearance
  • Serum albumin
  • Endoscopy and intestinal biopsies

Failure to Thrive of Non-CF Origin

• Clinical Features:
  • Poor weight gain without significant respiratory or gastrointestinal symptoms
• Distinguishing Points:
  • May be secondary to psychosocial factors, feeding difficulties, or undernutrition
• Investigations:
  • Sweat chloride testing to exclude CF
  • Nutritional and feeding assessments

Shwachman-Diamond Syndrome

• Clinical Features:
  • Pancreatic insufficiency
  • Neutropenia and bone marrow dysfunction
  • Skeletal abnormalities
• Distinguishing Points:
  • No significant lung disease in early stages
  • Rare compared to CF
• Investigations:
  • Faecal elastase testing
  • Genetic testing for SBDS gene mutations
  • Full blood count and bone marrow evaluation

Alpha-1 Antitrypsin Deficiency

• Clinical Features:
  • Emphysema (often lower lobe predominant)
  • Chronic liver disease or cirrhosis
• Distinguishing Points:
  • Onset typically in adulthood but can present in children
  • Not associated with pancreatic insufficiency or meconium ileus
• Investigations:
  • Serum alpha-1 antitrypsin levels
  • Phenotyping or genotyping

Bronchiectasis (Non-CF Causes)

• Clinical Features:
  • Chronic productive cough, haemoptysis, recurrent chest infections
• Distinguishing Points:
  • Consider in older children/adults with focal bronchiectasis and normal sweat test
  • Secondary to post-infectious damage, immune deficiency, or congenital syndromes
• Investigations:
  • High-resolution chest CT scan
  • Immune work-up

Management

Principles of Management

• CF is a chronic, multisystem genetic condition managed through symptom control, prevention of complications, and multidisciplinary support.
• Primary goals include preservation of lung function, maintenance of nutritional status, prevention of infection, and addressing extrapulmonary manifestations.

Respiratory Management

Airway Clearance

• Initiated early, even in asymptomatic individuals, to reduce mucus accumulation and delay disease progression.
• Common methods include manual chest physiotherapy, active cycle of breathing techniques, autogenic drainage, PEP devices, flutter valves, and high-frequency chest wall oscillation (e.g. the Vest™).
• These techniques are often combined and tailored to patient age, disease severity, and preference.

Bronchodilators

• Short-acting agents like salbutamol are administered before hypertonic saline or airway clearance in patients with wheezing or confirmed bronchodilator responsiveness.

Mucolytics

• Dornase alfa reduces sputum viscosity by breaking down extracellular DNA; it is recommended for individuals aged ≥6 years with moderate-to-severe disease.
• Inhaled hypertonic saline enhances airway hydration and mucociliary clearance, with benefits observed even in preschool-aged children.

Non-Invasive Ventilation (NIV)

• Useful for patients with difficulty expectorating or advanced disease. Combined with oxygen, it improves gas exchange during sleep.

Antibiotic Therapy

Acute Exacerbations

• Mild episodes are treated with oral antibiotics ± inhaled therapy.
• Moderate to severe cases require intravenous antibiotics—typically a combination of aminoglycosides and beta-lactams—tailored to previous microbiology.
• Treatment duration is typically 10–14 days, and airway clearance frequency should be increased during exacerbations.

Chronic Infection

• Inhaled antibiotics such as tobramycin or aztreonam are used to suppress Pseudomonas aeruginosa colonisation.
• Long-term macrolides (e.g. azithromycin) are used for anti-inflammatory effect and exacerbation prevention in patients chronically colonised with Pseudomonas.

Antibiotic Monitoring and Adverse Effects

• Therapeutic drug monitoring is essential for aminoglycosides due to nephrotoxicity and ototoxicity risk.
• Repeated beta-lactam exposure increases hypersensitivity risk, typically presenting as rashes.
• Some agents, like linezolid, are associated with QT prolongation.

Anti-inflammatory Therapy

Macrolides

• Azithromycin reduces airway inflammation and exacerbations in chronic Pseudomonas colonisation; screening for non-tuberculous mycobacteria is recommended prior to use.

Ibuprofen

• High-dose ibuprofen slows lung function decline in children aged 6–18 years but is limited by gastrointestinal side effects.

Inhaled Corticosteroids

• Reserved for coexisting asthma or allergic bronchopulmonary aspergillosis. Routine use in CF lung disease is not supported.

CFTR Modulator Therapy

Ivacaftor

• Effective for gating mutations like G551D; improves lung function and weight in responsive genotypes. Not effective for F508del homozygotes.

Lumacaftor/Ivacaftor and Tezacaftor/Ivacaftor

• Dual corrector-potentiator combinations used in F508del homozygous patients. Provide modest improvement in respiratory outcomes and reduce exacerbations.

Elexacaftor/Tezacaftor/Ivacaftor

• Triple therapy approved for individuals with ≥1 F508del mutation. Offers superior efficacy across age groups, with benefits in lung function, weight gain, and reduction in pulmonary exacerbations.
• Monitor for liver function, cataracts, and potential neurocognitive or behavioural side effects.

Gastrointestinal and Nutritional Management

Pancreatic Insufficiency

• Treated with pancreatic enzyme replacement therapy (PERT) including lipase, protease, and amylase.
• Fat-soluble vitamins (A, D, E, K) are supplemented regularly; H2 blockers or PPIs may be used to optimise enzyme function.

Intestinal Obstruction

• Meconium ileus or distal intestinal obstruction syndrome is managed with osmotic agents and water-soluble contrast enemas. Surgery is reserved for complete obstruction or failure of medical therapy.

Gastro-Oesophageal Reflux

• Treated with H2 antagonists or PPIs. Refractory cases may be considered for surgical intervention.

Liver Disease

• Managed with ursodeoxycholic acid. Advanced disease warrants referral for transplant assessment.

Advanced Disease and Lung Transplantation

Referral Criteria

• Adults with FEV₁ <30% or children with FEV₁ <40% should be evaluated.
• Additional indicators include poor nutritional status, hypoxaemia, pulmonary hypertension, and low exercise tolerance.

Post-Transplant Considerations

• CF-specific care should continue after lung transplantation. Multidisciplinary follow-up ensures monitoring for extrapulmonary complications and medication adherence.

Palliative and Supportive Care

• Recommended in all stages of CF, particularly in advanced disease.
• Focuses on symptom control, psychosocial support, and advance care planning.
• Early integration of palliative care improves quality of life and reduces hospitalisations.

Overall Survival Outlook

• Cystic fibrosis remains a life-limiting condition with no definitive cure. However, the outlook has markedly improved over recent decades due to earlier diagnosis and advancements in medical care.
• Individuals born with CF today may have a projected life expectancy extending into their mid-50s or beyond, with some models suggesting a median survival beyond 65 years in high-resource settings.
• In registry data from countries such as the UK, Ireland, and Canada, median survival ranges from 44 to 52 years. In the United States, where CFTR modulator access is more widespread, median survival exceeds 40 years.
• Males generally have a slightly better survival rate than females, and socioeconomic status significantly influences prognosis, with lower survival associated with social deprivation.

Disease Progression and Variability

• Prognosis is influenced by multiple factors including genotype, age at diagnosis, adherence to treatment, nutritional status, and access to multidisciplinary care.
• Disease severity and progression vary widely:
  • Some individuals are diagnosed in infancy with severe symptoms.
  • Others with milder forms may not be diagnosed until adulthood and tend to have a more favourable prognosis.
• Respiratory disease severity is the strongest determinant of long-term survival.

Pulmonary Complications and Mortality

• Respiratory failure and cor pulmonale are the most common causes of death in CF.
• Lung involvement typically begins with bronchitis and bronchiolitis, progressing to bronchiectasis and chronic airway infection.
• Progressive lung damage eventually leads to respiratory insufficiency and right heart failure.
• Despite modern treatments, end-stage lung disease remains inevitable in many cases unless lung transplantation is performed.

Lung Transplantation

• Median survival post-lung transplantation is approximately 8.5 years.
• Transplantation is considered when FEV₁ drops below critical thresholds or when patients experience rapid clinical deterioration despite optimal therapy.

Gastrointestinal and Hepatobiliary Complications

• Pancreatic damage is common, often resulting in exocrine insufficiency and, in 8–12% of adults over 25, the development of CF-related diabetes mellitus.
• Liver disease is also significant, including fatty liver (affecting 30–60% of patients), focal biliary fibrosis, and multilobular cirrhosis. Portal hypertension may lead to fatal oesophageal variceal bleeding in advanced cases.
• Excessive enzyme supplementation may contribute to fibrosing colonopathy, while gastrointestinal symptoms may also include peptic ulcers, distal intestinal obstruction syndrome (DIOS), and rectal prolapse.

Reproductive Health

• Over 95% of males are infertile due to congenital bilateral absence of the vas deferens (CBAVD), though spermatogenesis is preserved.
• Female fertility is mildly reduced due to thickened cervical mucus and potential nutritional deficits; however, successful pregnancies are increasingly common, especially with improved therapies.

Nutritional and Growth Factors

• Lower body mass index (BMI), shorter stature, and reduced muscle mass are associated with poorer outcomes.
• Children with higher weight-for-age percentiles at 4 years demonstrate better lung function and survival into adulthood.
• Malnutrition, if unaddressed, contributes significantly to accelerated pulmonary decline.

Complications Impacting Prognosis

• Common and impactful complications include:
  • Heat stroke and salt depletion in infants due to sweat electrolyte abnormalities.
  • Mucocele-related sinus complications leading to CNS effects.
  • Gastro-oesophageal reflux, peptic ulceration, and recurrent intestinal obstruction.
  • Gallstones and cholecystitis, which occur more frequently in CF than in the general poplation.
  • Delayed puberty and impaired growth, particularly in adolescents.

Respiratory Complications

Chronic respiratory failure

• Develops in advanced CF lung disease.
• Hypercapnia may remain stable for years; eventual need for oxygen therapy or non-invasive ventilation.

Acute respiratory failure

• Triggered by pulmonary exacerbations in severe disease.
• Manifests with hypoxaemia and hypercapnia; requires both supportive and causative management.

Pneumothorax and haemopneumothorax

• Associated with severe structural lung disease.
• Management depends on the extent of air leak.

Haemoptysis

• May range from minor blood-streaked sputum to massive bleeding.
• Life-threatening cases may need bronchial artery embolisation.

Cor pulmonale

• Up to 70% of patients with chronic hypoxaemia develop right ventricular hypertrophy.

Allergic bronchopulmonary aspergillosis (ABPA)

• Hypersensitivity reaction to Aspergillus fumigatus.
• Features include elevated IgE, specific IgG, wheezing, and central infiltrates.
• Treated with corticosteroids, antifungals, or both.

Obstructive sleep apnoea and sleep disturbance

• Occurs regardless of lung function severity.
• Presents with altered sleep architecture; requires evaluation for disordered breathing.

Chronic rhinosinusitis and nasal polyps

• Chronic sinus opacification is universal, but symptomatic rhinosinusitis is variable.
• Nasal polyps may require topical steroids or surgical excision.

Gastrointestinal Complications

Distal intestinal obstructive syndrome (DIOS)

• Results from inspissated stool and mucus in the terminal ileum.
• Managed with laxatives, contrast enemas, or nasogastric interventions.

Constipation

• Affects 10–57% of individuals, especially those with pancreatic insufficiency and inadequate enzyme therapy.
• Needs treatment to prevent progression to DIOS.

Intussusception

• Most commonly ileocolic.
• Requires air enema or surgery.

Rectal prolapse

• Usually presents in undiagnosed children under three years of age.

Acute and recurrent pancreatitis

• Occurs mainly in pancreatic-sufficient patients.
• Associated with defective CFTR-mediated bicarbonate conductance.

Hepatobiliary Complications

Advanced liver disease

• Includes biliary fibrosis, cirrhosis, portal hypertension, and hepatic encephalopathy.
• Treated with bile acids (e.g., ursodeoxycholic acid); transplant assessment in decompensated cases.

Gastrointestinal cancers

• Colorectal cancer risk is 5–10 times higher in CF patients and up to 30 times in transplant recipients.
• Screening is recommended from age 40, earlier post-transplant.

Nutritional and Endocrine Complications

Failure to thrive and short stature

• Due to increased caloric needs and malabsorption.
• Requires calorie-dense diets, supplements, and sometimes gastrostomy feeding.

Delayed puberty

• Common in both sexes due to malnutrition and chronic illness.

CF-related diabetes mellitus (CFRD)

• Affects ~40% of individuals over age 30.
• Features overlap with type 1 and 2 diabetes; insulin is the mainstay of treatment.

Metabolic alkalosis

• Often secondary to electrolyte losses through sweat or gastrointestinal fluid losses.

Rickets and osteoporosis

• Related to malabsorption, corticosteroid use, delayed puberty, and inflammation.
• Treated with vitamin D, calcium, and bisphosphonates.

Urolithiasis

• Stones occur in ~4.6% of CF patients, with a third requiring surgical intervention.

Musculoskeletal and Joint Complications

Hypertrophic osteoarthropathy

• Presents with pain and swelling in distal long bones, more common in those over 12.

Arthritis

• Often transient, particularly affecting the knees; may have polyarticular patterns.

Mental Health Complications

Depression and anxiety

• Affect both patients and caregivers, with depression impacting adherence, nutrition, and lung function.
• Screening should begin in childhood, and psychological support should be offered as needed.

Treatment-Related Complications

Drug-related hearing loss

• Linked to aminoglycoside use; regular auditory screening recommended.

Nephrotoxicity

• Related to aminoglycosides and vancomycin.
• Requires serum creatinine monitoring and dose adjustment.

1. Aaron SD, Vandemheen KL, Freitag A, et al. Treatment of pulmonary exacerbations in cystic fibrosis: a comparison of home and hospital therapy. Am J Respir Crit Care Med. 2005;171(9):954–960.
2. American Thoracic Society/European Respiratory Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. Am J Respir Crit Care Med. 2000;161(2 Pt 1):646–664.
3. Barben J, Castellani C, Munck A, et al. Updated guidance on the management of children with CFTR-related metabolic syndrome/CFSPID. J Cyst Fibros. 2021;20(5):810–819.
4. Bodewes FAJA, Wilschanski M. CFTR dysfunction and its impact on the pancreas. Pancreapedia: Exocrine Pancreas Knowledge Base. 2015.
5. Berke G, Gede N, Szadai L, et al. Bicarbonate defective CFTR variants increase risk for chronic pancreatitis: a meta-analysis. PLoS One. 2022;17(10):e0276397.
6. Bush A, Chodhari R, Collins N, et al. Primary ciliary dyskinesia: current state of the art. Arch Dis Child. 2007;92(12):1136–1140.
7. Castellani C, Cuppens H, Macek M Jr, et al. Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice. J Cyst Fibros. 2008;7(3):179–196.
8. Castellani C, Picci L, Tamanini A, et al. Association between carrier screening and incidence of cystic fibrosis. JAMA. 2009;302(23):2573–2579.
9. Ciofu O, Hansen CR, Høiby N. Respiratory bacterial infections in cystic fibrosis. Curr Opin Pulm Med. 2013;19(3):251–258.
10. Collaco JM, McGready J, Green DM, et al. Effect of secondhand smoke exposure on lung function in patients with cystic fibrosis. Am J Respir Crit Care Med. 2008;178(12):1221–1226.
11. Conner GE, Wijkstrom-Frei C, Randell SH, et al. The lactoperoxidase system links anion transport to host defense in cystic fibrosis. FEBS Lett. 2007;581(2):271–278.
12. Cutting GR. Cystic fibrosis genetics: from molecular understanding to clinical application. Nat Rev Genet. 2015;16(1):45–56.
13. Cutting GR. Modifier genes in Mendelian disorders: the example of cystic fibrosis. Ann N Y Acad Sci. 2010;1214:57–69.
14. Davies JC, Alton EW, Bush A. Cystic fibrosis. BMJ. 2007;335(7632):1255–1259.
15. De Boeck K, Vermeulen F, Wanyama S, Thomas M. Clinical implications of variants of CFTR in individuals with diagnostic characteristics of CF. Thorax. 2020;75(3):267–273.
16. Derichs N. Targeting a genetic defect: cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis. Eur Respir Rev. 2013;22(127):58–65.
17. Dodge JA, Lewis PA, Stanton M, Wilsher J. Cystic fibrosis mortality and survival in the UK: 1947–2003. Eur Respir J. 2007;29(3):522–526.
18. Elborn JS. Cystic fibrosis. Lancet. 2016;388(10059):2519–2531.
19. 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.
20. Farrell PM, Rosenstein BJ, White TB, et al. Guidelines for diagnosis of cystic fibrosis in newborns through older adults: Cystic Fibrosis Foundation consensus report. J Pediatr. 2008;153(2):S4–S14.
21. Flume PA, Mogayzel PJ Jr, Robinson KA, et al. Cystic fibrosis pulmonary guidelines: pulmonary complications: hemoptysis and pneumothorax. Am J Respir Crit Care Med. 2010;182(3):298–306.
22. Flume PA, Van Devanter DR, Conrad D, et al. Consensus approaches to standardise pulmonary exacerbation management. J Cyst Fibros. 2021;20(3):S45–S54.
23. Gonska T, et al. CFTR gene variant testing: impact on newborn screening and diagnosis. Pediatr Pulmonol. 2015;50(10):948–955.
24. Groves T, Skierka A, Rowe SM. Newborn screening for cystic fibrosis: implementation, access, and outcomes. Pediatr Clin North Am. 2015;62(3):587–604.
25. Hamosh A, FitzSimmons SC, Macek M Jr, Knowles MR, Rosenstein BJ, Cutting GR. Comparison of the clinical manifestations of cystic fibrosis in black and white patients. J Pediatr. 1998;132(2):255–259.
26. Hartl D, Gaggar A, Bruscia E, et al. Innate immunity in cystic fibrosis lung disease. J Cyst Fibros. 2012;11(5):363–382.
27. Heneghan M, Southern KW, Murphy J, et al. Corrector therapies (with or without potentiators) for people with cystic fibrosis with class II CFTR gene variants (most commonly F508del). Cochrane Database Syst Rev. 2023;11:CD010966.
28. Joo NS, Irokawa T, Robbins RC, et al. Hyposecretion, not hyperabsorption, is the basic defect of cystic fibrosis airway glands. J Biol Chem. 2006;281(11):7392–7398.
29. Kelly A, Hawkes CP, McCourt M, et al. Bone health in children with cystic fibrosis. J Cyst Fibros. 2019;18(4):524–531.
30. Kerem E, Reisman J, Corey M, et al. Prediction of mortality in patients with cystic fibrosis. N Engl J Med. 1992;326(18):1187–1191.
31. Konstan MW, Butler SM, Wohl ME, et al. Growth and nutritional indexes in early life predict pulmonary function. J Pediatr. 2003;142(6):624–630.
32. Konstan MW, Morgan WJ, Butler SM, et al. Risk factors for rate of decline in FEV1 in children and adolescents with cystic fibrosis. J Pediatr. 2007;151(2):134–139.e1.
33. Koutsokera A, Varughese RA, Sykes J, et al. Pre-transplant factors associated with mortality after lung transplantation. J Cyst Fibros. 2019;18(3):407–415.
34. LiPuma JJ. The changing microbial epidemiology in cystic fibrosis. Clin Microbiol Rev. 2010;23(2):299–323.
35. Lands LC, St-Jean M, Thibodeau M, et al. Pancreatic function in cystic fibrosis patients with meconium ileus. J Pediatr. 1992;121(3):439–443.
36. Matsui H, Grubb BR, Tarran R, et al. Evidence for periciliary liquid layer depletion, not abnormal ion composition, in the pathogenesis of cystic fibrosis airways disease. Cell. 1998;95(7):1005–1015.
37. Mall MA, Mayer-Hamblett N, Rowe SM. Cystic fibrosis: emergence of highly effective targeted therapeutics and potential clinical implications. Am J Respir Crit Care Med. 2020;201(10):1193–1208.
38. Moskwa P, Lorentzen D, Excoffon KJ, et al. A novel host defense system of airways is defective in cystic fibrosis. Am J Respir Crit Care Med. 2007;175(2):174–183.
39. O'Sullivan BP, Freedman SD. Cystic fibrosis. Lancet. 2009;373(9678):1891–1904
40. Ren CL, Borowitz DS, Gonska T, et al. CFTR-related metabolic syndrome and CF screen positive, inconclusive diagnosis. J Pediatr. 2017;181S:S45–S51.e1.
41. Ren CL, Morgan RL, Oermann CM, et al. Evidence-based clinical practice guideline for the screening and treatment of depression and anxiety in individuals with cystic fibrosis. Thorax. 2019;74(Suppl 1):i1–i9.
42. Rosenfeld M, Davis R, FitzSimmons S, Pepe M, Ramsey B. Gender gap in cystic fibrosis mortality. Am J Epidemiol. 1997;145(9):794–803.
43. Rosenstein BJ, Cutting GR. The diagnosis of cystic fibrosis: a consensus statement. J Pediatr. 1998;132(4):589–595.
44. Rowe SM, Miller S, Sorscher EJ. Cystic fibrosis. N Engl J Med. 2005;352(19):1992–2001.
45. Scotet V, L'Hostis C, Férec C. The changing epidemiology of cystic fibrosis: incidence, survival and impact of the CFTR gene discovery. Genes (Basel). 2020;11(6):589.
46. Shah GB, De Keyzer L, Russell JA, et al. Treatment of chronic rhinosinusitis with dornase alfa. Int Forum Allergy Rhinol. 2018;8(6):729–736.
47. Southern KW, Barker PM, Solis-Moya A, Patel L. Macrolide antibiotics for cystic fibrosis. Cochrane Database Syst Rev. 2012;11:CD002203.
48. Stephenson AL, Sykes J, Stanojevic S, et al. Survival comparison of patients with cystic fibrosis in Canada and the United States: a population-based cohort study. Ann Intern Med. 2017;166(8):537–546.
49. Wang Y, Loo TW, Bartlett MC, Clarke DM. Modulating the folding of CFTR. J Biol Chem. 2007;282(51):37241–37249.
50. Wanner A, Salathe M, O'Riordan TG. Mucociliary clearance in the airways. Am J Respir Crit Care Med. 1996;154(6 Pt 1):1868–1902.
51. Wucherpfennig L, Wuennemann F, Eichinger M, et al. Longitudinal magnetic resonance imaging detects onset and progression of chronic rhinosinusitis. Ann Am Thorac Soc. 2023;20(5):687–697.
52. Zielenski J. Genotype and phenotype in cystic fibrosis. Respiration. 2000;67(2):117–133.