Best Test for Diagnosing Cystic Fibrosis
The sweat chloride test is the gold standard diagnostic test for cystic fibrosis, with values ≥60 mmol/L confirming the diagnosis when combined with clinical features or positive newborn screening. 1
Diagnostic Algorithm
Primary Diagnostic Test: Sweat Chloride Test
The sweat chloride test remains the most reliable and widely available diagnostic test for CF, performed via pilocarpine iontophoresis with collection on gauze, filter paper, or Macroduct coil. 2
A sweat chloride concentration ≥60 mmol/L is diagnostic for CF when the patient has clinical features consistent with CF, a positive family history, or a positive newborn screening result. 1
Sweat testing should be performed bilaterally in newborns weighing >2 kg and at least 36 weeks corrected gestational age, ideally after 10 days of age but by the end of the neonatal period (4 weeks). 1
Sweat chloride values of 30-59 mmol/L are considered intermediate/ambiguous and require repeat testing, as infants with CF often initially present with values in this range. 1
Complementary Genetic Testing
CFTR genetic testing via blood test or cheek swab should be performed to identify disease-causing mutations, with identification of two CF-causing mutations confirming the diagnosis regardless of sweat test results. 1
For individuals with CRMS/CFSPID (screen-positive, inconclusive diagnosis) who have <2 disease-causing variants identified by newborn screening, CFTR sequencing including intronic regions should be performed. 1
Full-gene sequencing of coding and flanking regions plus deletion/duplication analysis should be offered selectively to clarify diagnosis in ambiguous cases. 1
Clinical Evaluation Requirements
- Diagnosis requires BOTH clinical presentations of disease (chronic respiratory symptoms, pancreatic insufficiency, or other CF features) AND evidence of CFTR dysfunction (elevated sweat chloride or two CF-causing mutations). 1
Important Diagnostic Pitfalls
False Negatives with Sweat Testing
Normal sweat chloride values do not absolutely exclude CF diagnosis in atypical cases with mild phenotypes—maintain high clinical suspicion and pursue alternative testing if clinical features strongly suggest CF. 3
Patients with compound heterozygous mutations (e.g., ΔF508/3849+10kb C→T) can present with normal sweat chloride values but still develop progressive bronchiectasis and Pseudomonas colonization. 3
Technical Considerations
Sweat analysis must be performed within a few hours of collection to ensure accuracy. 1
Not all infants produce sufficient sweat quantities for reliable testing, particularly those <2 weeks old or <2 kg body weight. 1
When sweat sodium values are 30-70 mmol/L, repeat testing and measure both sodium and chloride for optimal discrimination, as 5% of CF patients may have initial values below 50 mmol/L. 4
Newborn Screening Context
Newborn screening uses immunoreactive trypsinogen (IRT) as the initial test, but elevated IRT is NOT diagnostic—it can be elevated due to prematurity, stressful delivery, or carrier status. 1
All positive newborn screens require confirmatory sweat chloride testing before CF diagnosis can be made. 1
Screening algorithms vary by state/country, using either IRT/repeat IRT protocols or IRT/DNA mutation analysis, but all require sweat testing for definitive diagnosis. 1
Advanced Testing for Ambiguous Cases
When diagnostic criteria are not met despite clinical suspicion (intermediate sweat chloride, <2 mutations identified), referral to expert centers for bioassays of CFTR function is recommended, including nasal potential difference measurement or intestinal current measurement. 2
In vivo demonstration of characteristic abnormalities in ion transport across nasal epithelium can serve as diagnostic evidence when other criteria are inconclusive. 1