Cystic fibrosis (CF) is an autosomal recessive disorder that is common in individuals of European descent. It is caused by mutations in the CFTR gene, which encodes the CF transmembrane conductance regulator (CFTR) protein. These mutations result in defective chloride (Cl-) channels. Mandated newborn screening (NBS) in many countries can frequently detect CF during the asymptomatic newborn period. Initial manifestations may include meconium ileus, failure to thrive, and symptoms of malabsorption, and later in life, patients may experience symptoms such as recurrent respiratory infections, recurrent pancreatitis, and infertility. As the disease progresses, defective Cl- channels in the respiratory tract result in thickened bronchial mucus and impaired mucociliary clearance, which leads to chronic respiratory infections, pulmonary colonization with multiresistant bacteria, and a progressive decline in lung function. Patients often experience acute episodes of worsening respiratory symptoms, known as pulmonary exacerbations. CFTR dysfunction in the exocrine pancreas and biliary tract can ultimately lead to CF-related liver disease (CFLD) and CF-related diabetes (CFRD). If CF is suspected, the first diagnostic study is a sweat test, usually followed by genetic testing, and if the diagnosis remains unclear, CFTR physiologic testing. Patients with CF should be managed at a CF-accredited center, if possible. Management should focus on slowing the progression of lung disease, eradicating and/or suppressing chronic infections, preventing and/or treating exacerbations, and addressing complications and comorbidities. Many patients may also benefit from novel treatments such as CFTR modulators, which can partially restore CFTR function. With the recent advances in treatment, the predicted median life expectancy of a patient born in 2021 with CF is estimated to be ∼ 45 years. Complications due to lung disease are the most common cause of death in CF.
- Second most common genetic metabolic disorder; after hemochromatosis in individuals of Northern European descent. 
- Incidence: approx. 1:3500 in the US 
Epidemiological data refers to the US, unless otherwise specified.
- CF is a hereditary autosomal recessive disorder caused by defective CFTR (cystic fibrosis transmembrane conductance regulator) protein due to mutation in the CFTR gene located on the long arm of chromosome 7. 
- The most common mutation causing CF is delta F508 (ΔF508), a codon deletion that leads to the absence of phenylalanine (F) in position 508 of the CFTR protein.
Children whose parents are both heterozygous carriers of cystic fibrosis have a 25% chance of being affected by the condition.
- The CFTR gene encodes the CFTR protein, which is an important component of the ATP-gated chloride channel in cell membranes.
- Mutated CFTR gene → misfolded protein → retention for degradation of the defective protein in the rough endoplasmic reticulum (rER) → absence of ATP-gated chloride channel on the cell surface of epithelial cells throughout the body (e.g., intestinal and respiratory epithelia, sweat glands, exocrine pancreas, exocrine glands of reproductive organs) 
In sweat glands
- The chloride channel is responsible for transporting Cl- from the lumen into the cell (reabsorption).
- Defective ATP-gated chloride channel → inability to reabsorb Cl- from the lumen of the sweat glands → reduced reabsorption of Na+ and H2O → excessive loss of salt and elevated levels of NaCl in sweat
In all other exocrine glands (e.g., in the GI tract or lungs)
- The chloride channel is responsible for transporting Cl- from the cell into the lumen (secretion).
- Defective ATP-gated chloride channel → inability to transport intracellular Cl- across the cell membrane → reduced secretion of Cl- and H2O → accumulation of intracellular Cl- → ↑ Na+ reabsorption (via ENaC); → ↑ H2O reabsorption; → formation of hyperviscous mucus → accumulation of secretions and blockage of small passages of affected organs → chronic inflammation and remodeling → organ damage (see “Clinical features” below)
- ↑ Na+ reabsorption → transepithelial potential difference between interstitial fluid and the epithelial surface increases; (i.e., negative charge increases; e.g., from normal -13 mv to abnormal -25 mv)
- CF pulmonary exacerbations: episodes of acute worsening of respiratory symptoms (e.g., increased cough and sputum production, fever, dyspnea, hemoptysis) in patients with CF, which can result in an irreversible decline in lung function 
- CF-related diabetes (CFRD): Pancreatic exocrine dysfunction leads to pancreatic damage, which destroys the pancreatic endocrine insulin-producing beta cells and results in insulin deficiency. 
- CF-related liver disease (CFLD): Exocrine complication of CF that can include neonatal obstructive cholestasis, cholelithiasis, biliary cirrhosis, portal hypertension, and end-stage liver disease 
Gastrointestinal symptoms are common in children. The presence of these features during infancy should raise suspicion for CF.
- Meconium ileus (in newborns)
- Failure to thrive (due to malabsorption)
Exocrine pancreatic insufficiency
- Foul-smelling steatorrhea (fatty stools) may occur.
- Abdominal distention
- Deficiency of fat-soluble vitamins
- CF-related diabetes mellitus (CFRD) 
Liver and bile duct abnormalities
- Cholecystolithiasis, cholestasis
- Fatty metamorphosis of the liver, eventually progressing to liver cirrhosis
- Biliary cirrhosis; with portal hypertension, jaundice, and/or esophageal varices
- Intestinal obstruction: abdominal distention, pain, and a palpable mass
- Rectal prolapse (rare)
In almost all cases of meconium ileus, cystic fibrosis is the underlying disease.
Respiratory symptoms are common in adulthood. CF should be considered in individuals with the following features:
- Chronic obstructive lung disease with bronchiectasis
- Chronic sinusitis: nasal polyps may eventually develop
Recurrent or chronic productive cough and pulmonary infections
- S. aureus is the most common cause of recurrent pulmonary infection in infancy and childhood.
- P. aeruginosa is the most common cause of recurrent pulmonary infections in adulthood.
- Other commonly involved bacteria
- Burkholderia cepacia: can lead to cepacia syndrome, a severe necrotizing pneumonia that is often accompanied by rapid respiratory decline and can progress to sepsis 
- S. pneumoniae
- H. influenzae
- Increased susceptibility of individuals with CF to opportunistic, potentially life-threatening pathogens (e.g., Pseudomonas aeruginosa, Aspergillus)
- Infections with Pseudomonas aeruginosa → rapid decline in pulmonary function (patients with CF go through multiple antibiotic courses in their lifetime → increasing resistance of Pseudomonas aeruginosa to commonly used antibiotics) 
- A chronic infection with Aspergillus species may lead to allergic bronchopulmonary aspergillosis (see “Complications” below)
- Pulmonary obstruction and airway hyperreactivity may manifest with expiratory wheezing and/or dyspnea.
- Barrel chest , moist rales (indicate pneumonia), hyperresonance to percussion
- Signs of chronic respiratory insufficiency: digital clubbing associated with chronic hypoxia
- Particularly salty sweat
- Possible electrolyte wasting
- Frequent fractures due to osteopenia
Men: usually infertile
- Obstructive azoospermia; is common, spermatogenesis may be intact
- The vas deferens may be absent.
- Undescended testicle
Women: reduced fertility
- Viscous cervical mucus can obstruct fertilization.
- Menstrual abnormalities (e.g., amenorrhea)
- Delayed development of secondary sexual characteristics
- Men: usually infertile
Newborn screening (NBS) for CF is essential for early detection and treatment, which can improve health outcomes. In many countries, including the US, it is mandatory to screen for CF. 
- Sample collection: newborn blood spot test, performed via heel prick blood sampling in the first 24 and 48 hours of life
Screening tests 
Immunoreactive trypsinogen (IRT) : initial screening test
- An immunofluorescence assay that measures levels of IRT 
- Normal IRT levels: CF unlikely
- Elevated IRT levels: CF possible; additional screening tests required 
- CFTR mutation testing (DNA testing): second-tier screening test
- Immunoreactive trypsinogen (IRT) : initial screening test
- Screening protocols: a combination of CF screening methods to minimize false-positive and false-negative NBS results 
- Next steps after positive NBS: Refer patients promptly to a specialist for a complete diagnostic workup and to start treatment if required.
Patients who test positive for CF during NBS should undergo a sweat test, ideally in the first 4 weeks of life. 
Patients with a presumptive diagnosis of CF (i.e., meconium ileus, positive NBS result with suggestive symptoms, or two CF-causing mutations detected during NBS) should immediately be referred to a specialized center and ideally evaluated within 24–72 hours. 
Diagnosis of CF is based on clinical findings and evidence of CFTR protein dysfunction.
- Presence of any of the following requires a follow-up with confirmatory testing:
- Positive newborn screening (NBS)
- First-degree family member with CF
- Typical clinical features of CF (e.g., chronic sinopulmonary disease, gastrointestinal and nutritional irregularities, syndromes of salt loss, obstructive azoospermia)
Any of the following findings are evidence of CFTR protein dysfunction:
- Sweat chloride testing with a chloride value ≥ 60 mmol/L
- Evidence of two CF-causing CFTR gene mutations and a sweat chloride test result ≥ 30 mmol/L
- Positive physiologic CFTR testing with abnormal nasal potential difference test or intestinal current measurement
All patients with suspected CF should undergo a sweat test and CFTR genetic testing to help identify mutations that may affect management. 
|Confirmatory testing for CF |
|Order of testing||Results||Next steps|
Sweat test (initial test)
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CFTR mutation analysis
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|CFTR full gene analysis|| || |
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CFTR physiologic testing
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Ideally, all patients with a confirmed diagnosis of CF should be evaluated at a specialized center (e.g., an accredited CF center) within 24–72 hours of diagnosis. 
Sweat test (quantitative pilocarpine iontophoresis) 
- Indications: preferred initial test in all patients with suspected CF
- Method 
- Pilocarpine and an electrical current are applied to the skin to stimulate sweat production.
- Sweat is collected with absorbent pads and the Cl- concentration is measured.
CFTR dysfunction is confirmed with a positive sweat test (≥ 60 mmol/L). If the result is borderline (30–59 mmol/L), proceed to genetic testing and, if the diagnosis is still unclear, consider physiologic testing (NPD or ICM).
In most exocrine glands, intracellular Cl- is transported across the cell membrane into the lumen through the CFTR Cl- channel. In sweat glands, Cl- is transported in the opposite direction, from the lumen into the cell. In CF, a defect in the CFTR Cl- channel results in an accumulation of Cl- and, subsequently, of Na+ in the lumen of the sweat gland, leading to an increased concentration of NaCl in the sweat.
CFTR genetic testing 
- Carrier screening
- Confirmatory test after equivocal sweat test
- Guidance of targeted therapy (e.g., CFTR modulators)
Physiologic testing 
- Exposing specific tissues to different standardized solutions results in predictable ion movements and voltage changes.
- Ionic charges and voltage responses can be measured and compared with standard reference ranges for patients with and without CF.
Nasal potential difference test
- In vivo assessment of CFTR function in the respiratory epithelium, performed in the nasal cavity
- Results include e.g., more negative baseline potential difference and no difference in nasal potential difference after administration of a chloride-free solution
- Intestinal current measurement: ex vivo assessment of CFTR function in the intestinal epithelium, performed in a fresh rectal biopsy sample
- Nasal potential difference test
The pulmonary status of all patients with CF should be assessed at the time of diagnosis using pulmonary function tests (PFTs) and imaging, in addition to microbiological studies to detect respiratory pathogens. These studies should be repeated regularly to monitor for disease progression, which allows for early initiation of any required interventions.
Pulmonary function tests: indicated at diagnosis and repeated every 3 months for monitoring
- Modalities: predominantly spirometry in patients ≥ 6 years of age 
- Findings: obstructive pattern, e.g., ↓ FEV1:FVC ratio (see “Obstructive lung diseases”) 
Imaging: chest x-ray or chest CT are indicated at baseline and every 2–4 years in patients with stable lung function
- Early findings: may be normal or show subtle signs of air trapping and hyperinflation
- Late findings
- Signs of obstructive lung disease (e.g., air trapping, hyperinflation)
- Reticular nodular pattern
Microbiology: findings can help prevent and treat exacerbations 
- Bacterial sputum cultures most commonly show growth of some of the following pathogens:
- Gram positive: Staphylococcus aureus
- Gram negative: Hemophilus influenzae, Pseudomonas aeruginosa (a defining pathogen in CF), Burkholderia cepacia , Achromobacter spp., and Stenotrophomonas maltophilia
- Additional studies include: sputum smear and culture for acid-fast bacilli, fungal cultures
- Bacterial sputum cultures most commonly show growth of some of the following pathogens:
Monitoring with sputum cultures helps guide the selection of antibiotics to prevent and treat exacerbations. 
Pseudomonas, Stenotrophomonas, and/or Burkholderia infections are associated with rapid lung function deterioration and higher rates of lung transplantation. 
Additional screening and monitoring
- Routine laboratory studies
- CBC: may show anemia; potentially leukocytosis during exacerbations
- BMP: findings are variable, e.g., contraction alkalosis and hypokalemia
- Nutritional assessment
- Weight, height, and head circumference
- Blood tests: total protein and albumin (typically low), fat-soluble vitamins
- Stool tests: low levels of pancreatic elastase suggest exocrine pancreatic insufficiency
- Liver chemistries and coagulation panel: to assess liver function and screen for CF-related liver disease (CFLD)
- Fasting glucose: as a part of the screening for CF-related diabetes (CFRD)
- Audiology exam
- CT head may show opacification of sinuses in patients with features of chronic sinusitis
- Routine laboratory studies
Sweat losses of NaCl and H2O lead to contraction of the ECF volume and RAAS activation (similar to the effects of loop diuretics). This can result in increased renal reabsorption of NaCl and H2O and excretion of H+ and K+, causing alkalosis and hypokalemia.
General principles 
- All patients with CF require periodic follow-up with a multidisciplinary team for specialized management.
- Management should include the following goal-directed interventions:
- Preservation of lung function
- Pharmacological and nonpharmacological interventions
- Prevention of infection and reduction of exacerbations
- Optimization of nutrition
- Screening and monitoring for comorbidities and complications
- Preservation of lung function
- Patients with certain mutations may benefit from treatment with CFTR modulators.
- Acute pulmonary exacerbations require rapid and effective treatment.
Preservation of lung function 
Lung function is preserved by combining pharmacological and nonpharmacological interventions to improve mucociliary clearance, reduce mucus viscosity, and mobilize secretions.
Pharmacological interventions 
High-dose ibuprofen: can slow the progression of lung disease
- Indication: Consider in patients 6–17 years of age with mild disease (FEV1 > 60% of predicted).
- Avoid in patients with a history of hemoptysis.
Bronchodilators: SABA (e.g., albuterol), LABA (e.g., salmeterol)
- SABA indications: prior to inhaled therapies and/or chest physiotherapy , patients with episodes of airway hyperresponsiveness
- Long-term use is not routinely recommended 
- Hypertonic saline nebulization; (6–7% NaCl): mucociliary and osmotic effect; that can improve mucociliary clearance and thin the mucus 
- Dornase alfa, aerosolized : a recombinant DNase that thins the mucus by breaking down extracellular DNA in sputum 
- Other therapies
- N-acetylcysteine: efficacy is unproven in CF 
- Corticosteroids (inhaled and systemic): insufficient evidence; not routinely used 
Airway clearance techniques: a mainstay of CF treatment that loosens and mobilizes mucus secretions
- Conventional chest physiotherapy (CPT): postural drainage with percussion and/or clapping
- Alternative airway clearance methods
- High-frequency chest compression
- Airway oscillating devices
- Positive expiratory pressure devices
- Huff coughing
- Exercise (e.g., swimming, jogging, cycling)
Patients with CF benefit from a regular airway clearance routine that combines pharmacological measures with airway clearance techniques to preserve lung function and reduce symptoms. 
An airway clearance session generally begins with SABA therapy to open the airways, followed by mucolytics to thin the mucus, then airway clearance techniques. 
Prevention of infection and reduction of exacerbations in CF 
- Pulmonary exacerbations in patients with CF are often triggered by chronic lung infections of pathogenic organisms.
- Eradication and/or suppression regimens can prevent exacerbations and improve lung function.
- Consider treatment after early detection of relevant pathogens during routine surveillance sputum cultures.
- Eradication regimens include:
- P. aeruginosa: inhaled tobramycin
- MRSA: inhaled vancomycin PLUS oral antibiotics , PLUS extrapulmonary eradication
- Suppression regimens
- Indicated in patients with chronic infections
- May suppress the bacterial load, improve lung function, and/or prevent exacerbations
- Azithromycin: may be given long term, with benefits relying on its antiinflammatory effect 
Antibiotic eradication and suppression regimens for patients with CF should always be selected in consultation with a specialist.
Optimization of nutrition 
There is a direct correlation between BMI and pulmonary lung function in patients with CF. The following are common dietary recommendations for patients with CF:
- High-energy diet to compensate for increased demand (target BMI ≥ 50thpercentile) 
- Pancreatic enzyme supplements 
- Additional NaCl intake 
- Oral supplementation of fat-soluble vitamins (ADEK) 
CFTR modulators 
A relatively new therapy for the long-term management of CF that targets specific defects in the CFTR protein to improve its function.
- Approved for patients with specific CFTR mutations (e.g., ΔF508, G511D mutations)
- Their use can potentially reduce CF complications and comorbidities
Mechanism of action: improve CFTR protein function by targeting underlying protein defects 
- Potentiators (e.g., ivacaftor; ): increase CFTR Cl- channel gate opening and conductance and improve Cl- transport
- Correctors (e.g., lumacaftor; , tezacaftor, elexacaftor): improve protein folding, protein stability, and the transport of functional CFTR protein to the cell surface 
- Two or more CFTR modulators with different mechanisms of action can be combined to synergistically improve CFTR protein quantity and function.
- Combination therapy increases the yield of CFTR modulators and can therefore benefit larger numbers of patients. 
Perform CFTR genetic testing in all patients diagnosed with CF to assess for specific mutations that can be targeted by CFTR modulators.
CFTR modulators can improve FEV1, help patients gain weight, reduce exacerbations, and decrease sweat Cl- concentration. 
Additional measures 
Oxygen therapy: frequent oxygen monitoring and support for chronic respiratory insufficiency as needed
- Intermittent oxygen: indicated for desaturation during exercise and sleep
- Long-term oxygen: indicated for hypoxia on room air and borderline hypoxia with evidence of cor pulmonale
- A treatment option for patients with end-stage lung disease 
- Common indications for transplantation referral include:
- Low (< 30% of predicted) or rapidly declining FEV1
- Evidence of pulmonary hypertension
- Significant clinical decline.
- Provide emotional support and recommend additional mental health support to help patients manage their chronic condition and end-of-life care decisions. 
- Discuss the patient's long-term goals of care.
CF is a chronic, progressive, and ultimately life-shortening condition. Preferably, CF should be managed by a multidisciplinary team that can provide comprehensive care, which emphasizes shared decision-making.
Acute pulmonary exacerbations
General principles 
- Increased severity or new onset of clinical symptoms can be a sign of acute pulmonary exacerbation.
- Start culture-guided antibiotic therapy for pulmonary exacerbations.
- Additional measures
- Optimize nutrition.
- Increase airway clearance.
- Provide respiratory support as needed; see “Oxygen therapy” for details.
- Glucocorticoids: insufficient evidence, not routinely used
- Order inpatient contact precautions.
Treat pulmonary exacerbations quickly and aggressively to prevent an irreversible decline in lung function. 
Obtain a detailed clinical history, including the frequency and severity of respiratory symptoms. Patients may report weight loss, fever, and/or hemoptysis. Perform a thorough physical examination, paying particular attention to new auscultation findings and abnormal vital signs (e.g., increased respiratory rate, low oxygen saturation).
- Laboratory: CBC, BMP, liver chemistries, and consider blood gas
- Assess pulmonary status.
- Obtain new sputum cultures upon admission.
Antibiotic therapy in patients with CF is challenging because of a high prevalence of antibiotic resistance following frequent antibiotic use and the presence of multiple pathogenic organisms. Involve specialists early.
Choose initial antibiotics based on the speciation and sensitivities of the patient's recent routine sputum cultures. Adjust the antibiotics, if needed, once the results from the new sputum culture have been reported.
|Antibiotic therapy for CF pulmonary exacerbations |
|Pseudomonas aeruginosa|| |
|Other pathogens|| |
- Outpatient management: Specialists may provide ambulatory management for mild exacerbations with inhaled and/or oral antibiotics.
- Indications for inpatient management 
- Resistant bacteria with no PO antibiotic options
- Exacerbations with a poor response to outpatient management
- Moderate to severe disease or complicating comorbidities
- Critical care: Consider especially for young patients with a good baseline status and transplantation candidates.
Meconium ileus: failure to pass the first stool in neonates (meconium usually passes within the first 24–48 hours after birth)
- Etiology: Cystic fibrosis is the cause in > 90% of cases.
- Clinical findings: signs of a distal small bowel obstruction (thick meconium plugs the distal ileum)
X-ray abdomen (with contrast agent) 
- Dilated small bowel loops
- Microcolon: narrow caliber of the colon, as it is still unused (meconium has not been passed through yet)
- Neuhauser sign (soap bubble appearance): a mottled or bubble-like appearance in the distal ileum and/or cecum as a result of meconium mixing with swallowed air 
- Air-fluid levels are uncommon because of the viscous consistency of meconium.
- X-ray abdomen (with contrast agent) 
Differential diagnosis: See “Differential diagnosis of intestinal obstruction in neonates.”
- Enema with a contrast agent
- Surgery is required in complicated cases (e.g., intestinal perforation, volvulus)
- Small bowel obstruction: can also occur in older children and adults
Distal intestinal obstruction syndrome (DIOS) : blockage of the small intestines by thickened stool in the distal ileum and right colon 
- Highest prevalence in the second and third decades of life
- Tends to occur in individuals with pancreatic insufficiency
- Clinical manifestations include abdominal pain and distention, a palpable cecal mass, and flatulence.
- Allergic bronchopulmonary aspergillosis (ABPA): ∼ 10% of individuals with CF develop this condition. 
- Pulmonary emphysema
We list the most important complications. The selection is not exhaustive.
- Median life expectancy: 39 years 
- Individuals with CF who have pancreatic sufficiency tend to present with mainly pulmonary symptoms in late childhood/early adulthood and generally have a milder course of disease 
- The main determinant of life expectancy is the severity of pulmonary disease: chronic respiratory infections and mucus plugging → bronchiectasis (irreversible) → progressive respiratory failure → death
- Annual influenza vaccine for all affected individuals > 6 months with inactivated influenza vaccine
- Pneumococcal vaccine (see ”Immunization schedule”)
- Palivizumab: antibody against respiratory syncytial virus (RSV) for infants < 24 months
- Long-term treatment with azithromycin may be used to prevent recurrent pulmonary infections.