Diagnostics

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.

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, of Na+ in the lumen of the sweat gland, leading to an increased concentration of NaCl in the sweat.

• Indication

  • Carrier screening

  • Confirmatory test after equivocal sweat test

  • Guidance of targeted therapy (e.g., CFTR modulators)

• Modalities

  • CFTR mutation analysis: only tests for the most common CF-causing CFTR mutations

  • CFTR full gene analysis: includes gene sequencing and deletion/duplication analysis to detect less common CFTR mutations

• 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

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

  • Modalities: predominantly spirometry

  • Findings: obstructive pattern, e.g., ↓ FEV1:FVC ratio (see “Obstructive lung diseases”) [25][26]

• Imaging: chest x-ray or chest CT

  • 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

    • Bronchiectasis

• Microbiology: findings can help prevent and treat exacerbations [20][27]

  • Bacterial sputum cultures

Monitoring with sputum cultures helps guide the selection of antibiotics to prevent and treat exacerbations

• Routine laboratory studies

  • CBC: may show anemia; potentially leukocytosis during exacerbations

  • BMP: findings are variable, e.g., contraction alkalosis and hypokalemia

• Nutritional assessment

  • Stool tests: low levels of pancreatic elastase suggest exocrine pancreatic insufficiency

• CT head may show opacification of sinuses in patients with features of chronic sinusitis

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.