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Cystic fibrosis

Last updated: October 4, 2021

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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. [1][2][3]
  • Incidence: approx. 1:3,500 in the US [4]

Epidemiological data refers to the US, unless otherwise specified.

Children whose parents are both heterozygous carriers of cystic fibrosis have a 25% chance of being affected by the condition.

  • General considerations
  • 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)

Gastrointestinal [11]

Gastrointestinal symptoms are common in children. The presence of these features during infancy should raise suspicion for CF.

In almost all cases of meconium ileus, cystic fibrosis is the underlying disease.

Respiratory [11]

Respiratory symptoms are common in adulthood. CF should be considered in individuals with the following features:

Sweat glands

  • Particularly salty sweat
  • Possible electrolyte wasting

Musculoskeletal

Urogenital

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. [10][15]

  • Sample collection: newborn blood spot test, performed via heel prick blood sampling in the first 24 and 48 hours of life
  • Screening tests [16]
    • Immunoreactive trypsinogen (IRT) : initial screening test
    • CFTR mutation testing (DNA testing): second-tier screening test
      • Identifies the most common CF-causing CFTR mutations, including CF carriers [18]
      • Cannot detect uncommon CFTR mutations that are not included on the panel.
  • Screening protocols: a combination of CF screening methods to minimize false-positive and false-negative NBS results [18]
    • IRT/DNA protocol: If initial IRT levels are elevated, a CFTR mutation test is performed on the same sample.
    • IRT/IRT protocol: If initial IRT levels are elevated, a new sample is obtained and the test is repeated.
    • Other protocols: e.g., IRT/IRT/DNA, IRT/DNA/full-gene analysis
  • 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. [10]

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. [15]

Approach [15]

Diagnosis of CF is based on clinical findings and evidence of CFTR protein dysfunction.

All patients with suspected CF should undergo a sweat test and CFTR genetic testing to help identify mutations that may affect management. [15]

Confirmatory testing for CF [15][19]
Order of testing Results Next steps

Sweat test (initial test)
  • ≥ 60 mmol/L: CF confirmed
  • Refer for specialized management.
  • Proceed to CFTR mutation analysis.
  • 30–59 mmol/L: borderline result
  • Repeat sweat test and base next steps on the second result.
    • Borderline results from two sweat tests: Proceed to CFTR mutation analysis for diagnostic confirmation.
  • < 30 mmol/L: CF unlikely
  • Consider alternative diagnoses.

CFTR mutation analysis

  • Two CF-causing CFTR mutations: CF confirmed
  • Refer for specialized management.
  • One CF-causing CFTR mutation: diagnosis unclear
  • No CF-causing CFTR mutations: CF unlikely
  • Consider other diagnoses.
  • If clinical suspicion is very high: Obtain a CFTR full gene analysis and consider physiologic testing.
CFTR full gene analysis
  • Two CF-causing mutations: CF confirmed
  • Refer for specialized management.
  • One CF-causing mutation and a mutation with unknown clinical significance: diagnosis unclear
  • Proceed to physiologic testing
  • One CF-causing mutation with no alterations in the other CFTR copy: carrier status confirmed

CFTR physiologic testing

  • Positive: CF confirmed
  • Refer for specialized management.
  • Negative: CF unlikely
  • Consider other diagnoses.
  • Equivocal: diagnosis unclear
  • Refer to a specialized center for further evaluation.

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. [15]

Confirmatory tests

Sweat test (quantitative pilocarpine iontophoresis) [15]

  • Indications: preferred initial test in all patients with suspected CF
  • Method [10]
    • 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 Na+, in the lumen of the sweat gland, leading to an increased concentration of NaCl in the sweat.

CFTR genetic testing [15][20][21]

Physiologic testing [15][22][23]

  • Procedure
    • 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.
  • Modalities
    • 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

Additional investigations

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.

Monitoring with sputum cultures helps guide the selection of antibiotics to prevent and treat exacerbations. [20][27]

Pseudomonas, Stenotrophomonas, and/or Burkholderia infections are associated with rapid lung function deterioration and higher rates of lung transplantation. [27]

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 [20][28]

  • 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
  • Patients with certain mutations may benefit from treatment with CFTR modulators.
  • Acute pulmonary exacerbations require rapid and effective treatment.

Preservation of lung function [20][29][30]

Lung function is preserved by combining pharmacological and nonpharmacological interventions to improve mucociliary clearance, reduce mucus viscosity, and mobilize secretions.

Pharmacological interventions [20][29]

Nonpharmacological interventions

  • 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. [20][29]

An airway clearance session generally begins with SABA therapy to open the airways, followed by mucolytics to thin the mucus, then airway clearance techniques. [20][29]

Prevention of infection and reduction of exacerbations [20][27][29][30][31]

  • 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:
  • 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 [20][27][29][30]

Antibiotic eradication and suppression regimens for patients with CF should always be selected in consultation with a specialist.

Optimization of nutrition [32]

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:

CFTR modulators [28][34]

A relatively new therapy for the long-term management of CF that targets specific defects in the CFTR protein to improve its function.

  • Indications
    • 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 [29]
    • 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 [35]
  • Combination therapy
    • 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. [10]

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. [34]

Additional measures [20][36]

  • 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
  • Double-lung transplant
  • Provide emotional support and recommend additional mental health support to help patients manage their chronic condition and end-of-life care decisions. [30]
  • 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.

General principles [8][20][27]

  • Increased severity or new onset of clinical symptoms can be a sign of acute pulmonary exacerbation.
    • There are no universally accepted diagnostic criteria.
    • Findings are varied and include increased dyspnea or cough, changes in sputum production, weight loss, and fever
  • 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. [30]

Diagnostics [8][20][27]

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).

Antibiotics [27]

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 [27]
Pathogen Example regimens

Staphylococcus aureus

Pseudomonas aeruginosa
Other pathogens
  • H. influenzae: often susceptible to antipseudomonal antibiotics
  • Other gram-positive infections: should be covered by antibiotics that are used to treat S. aureus
  • Drug-resistant pathogens (e.g., B. cepacia, S. maltophilia, Achromobacter spp.)
    • Known to be resistant to many antibiotics and often require double coverage
    • Treatment should be decided in consultation with an infectious diseases specialist.

Disposition [8][20][27]

  • Outpatient management: Specialists may provide ambulatory management for mild exacerbations with inhaled and/or oral antibiotics.
  • Indications for inpatient management [8][20]
    • 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.

Gastrointestinal

Respiratory

We list the most important complications. The selection is not exhaustive.

  • Median life expectancy: 39 years [43]
  • 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 [44]
  • The main determinant of life expectancy is the severity of pulmonary disease: chronic respiratory infections and mucus plugging → bronchiectasis (irreversible) → progressive respiratory failure → death
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