What is the initial test to diagnose cystic fibrosis (CF)?

Sweat Chloride Test is the Initial Diagnostic Test for Cystic Fibrosis

The sweat chloride test is the gold standard initial test for diagnosing cystic fibrosis, performed via pilocarpine iontophoresis to collect and analyze sweat chloride concentration. 1

Diagnostic Testing Algorithm for Cystic Fibrosis

Primary Diagnostic Test

• Sweat Chloride Test
  • Collection method: Pilocarpine iontophoresis to stimulate sweat production
  • Collection system: Gauze pads, filter paper, or Macroduct coil
  • Analysis: Laboratory measurement of chloride content in collected sweat
  • Timing: Can be accurately performed on most infants by 2-3 weeks of age 1
  • Required sweat volume: Minimum of 15 μL (though newer technologies may require less) 2

Interpretation of Sweat Chloride Results

• Diagnostic values:
  • ≥60 mmol/L: Diagnostic of CF
  • 30-59 mmol/L: Intermediate range (requires further evaluation)
  • <30 mmol/L: CF unlikely 1

Confirmatory Testing

If sweat chloride results are intermediate or if clinical suspicion remains high despite normal sweat test:

1. Repeat sweat chloride test to confirm results
2. CFTR genetic analysis to identify disease-causing mutations
   • Initially test for common mutations
   • Extended analysis if only one or no mutations identified
3. CFTR functional analysis in specialized centers
   • Nasal potential difference measurement
   • Intestinal current measurement 3

Clinical Considerations

Test Accuracy and Reliability

• Sweat chloride testing has excellent diagnostic accuracy when performed according to standardized protocols
• The test should be performed according to approved procedural guidelines such as CLSI 2009 Guidelines 1
• Modern collection methods show strong correlation with the traditional Gibson Cooke method (r=0.85) 4

Special Populations

• Newborns:
  • For positive newborn screening results, sweat testing should be performed when infant weighs >2 kg and is at least 36 weeks corrected gestational age
  • Testing should be done as soon as possible after 10 days of age, ideally within the first 4 weeks 1
  • Bilateral testing recommended to increase likelihood of adequate specimen collection 1

Potential Pitfalls

• Insufficient sweat collection: More common in young infants, may necessitate repeat testing
• Intermediate results (30-59 mmol/L): Can be ambiguous, as these values may be seen in both classic and non-classic CF, or in non-CF conditions 1
• False negatives: Can occur in patients with specific CFTR mutations that produce milder phenotypes
• Technical errors: Improper collection, contamination, or analysis can affect results

Alternative Testing Methods

• Sweat conductivity shows promising results with high diagnostic accuracy (sensitivity 83.3%, specificity 99.7% at values >90 mmol/L) but is still considered a screening rather than diagnostic test by many authorities 5
• Wearable sensors for real-time measurement of sweat chloride are being developed, showing excellent agreement with standard methods (correlation coefficient 0.97) 2

Diagnostic Pathway

1. Initial presentation with symptoms suggestive of CF (respiratory symptoms, malabsorption, failure to thrive)
2. Perform sweat chloride test as the first-line diagnostic test
3. If sweat chloride ≥60 mmol/L: Diagnosis of CF is confirmed (when accompanied by clinical features or family history)
4. If sweat chloride 30-59 mmol/L: Proceed to genetic testing and possibly specialized CFTR functional testing
5. If sweat chloride <30 mmol/L but strong clinical suspicion: Consider genetic testing or repeat sweat testing

In more than 95% of cases, the diagnosis is straightforward with clear clinical presentation, sweat chloride >60 mmol/L, and identification of two disease-causing CFTR mutations 3. For the remaining cases with inconclusive results, referral to specialized CF centers for additional testing is essential.