What is the diagnostic approach for cystic fibrosis (CF) in patients of any age, including infants and those with a family history of the condition?

Diagnostic Approach for Cystic Fibrosis

The diagnosis of cystic fibrosis requires BOTH clinical evidence of disease (chronic respiratory symptoms, pancreatic insufficiency, positive family history, or positive newborn screening) AND laboratory confirmation of CFTR dysfunction through sweat chloride testing ≥60 mmol/L, identification of two CF-causing CFTR mutations, or demonstration of abnormal nasal epithelial ion transport. 1, 2

Initial Diagnostic Testing

Sweat Chloride Testing (Gold Standard)

Sweat chloride concentration ≥60 mmol/L is diagnostic for cystic fibrosis when combined with clinical features, positive family history, or positive newborn screening. 1, 3, 4

Technical requirements for sweat testing:

• Perform bilaterally in newborns weighing >2 kg and ≥36 weeks corrected gestational age 1, 3
• Test should occur after 10 days of age, ideally by 4 weeks of age in screen-positive newborns 1, 3
• Analysis must be completed within a few hours of sweat collection to ensure accuracy 1
• Use pilocarpine iontophoresis for sweat induction, with collection on gauze, filter paper, or Macroduct coil 4, 5

Interpretation of sweat chloride values:

• ≥60 mmol/L: Diagnostic for CF 1, 3
• 30-59 mmol/L: Intermediate/ambiguous range requiring repeat testing and extended CFTR gene analysis, as infants with CF often initially present in this range 1, 3, 6
• <30 mmol/L: CF unlikely, though may be reconsidered if clinical criteria and CFTR genotyping support CF 3

Important caveat: Not all infants produce sufficient sweat quantities for reliable testing, particularly those <2 weeks old or <2 kg body weight 1, 3

CFTR Genetic Testing

Identification of two CF-causing CFTR mutations confirms the diagnosis regardless of sweat test results. 1, 2

Testing approach:

• Perform via blood test or cheek swab 1
• Multi-gene panel testing using next-generation sequencing is preferred as initial test, detecting mutations in 70-90% of clinical CF cases 3
• The F508del mutation accounts for 30-88% of CF chromosomes depending on ethnicity, with approximately 85.5% of US patients carrying this variant 3, 7
• Over 2000 CFTR variants have been identified, though not all cause CF 3, 2

For individuals with screen-positive, inconclusive diagnosis (CRMS/CFSPID) with <2 disease-causing variants, CFTR sequencing including intronic regions should be performed. 1

Newborn Screening Protocol

Newborn screening uses immunoreactive trypsinogen (IRT) as the initial test, but elevated IRT is NOT diagnostic—it requires confirmatory sweat chloride testing. 1, 3

Screening algorithms vary by region:

• IRT/DNA: Initial IRT measurement followed by genetic analysis if above cut-off 3
• IRT/IRT: Initial IRT followed by repeat IRT on second specimen collected two weeks later 3
• IRT/pancreatitis-associated protein: Hybrid three-tiered approach 3

All positive newborn screens require confirmatory sweat chloride testing before CF diagnosis can be made. 1, 3

Clinical Evaluation

Look for these specific clinical presentations:

• Pulmonary manifestations: Chronic cough, wheezing, recurrent/persistent pulmonary infections, bronchiectasis 3, 7
• Gastrointestinal features: Meconium ileus (10-20% of newborns with CF), steatorrhea, poor weight gain, pancreatic insufficiency (85% of patients) 3, 7
• Other features: Chronic sinusitis, nasal polyps, congenital bilateral absence of vas deferens, elevated sweat salt loss 3

Physical examination findings:

• Hepatomegaly (sensitivity 60%, specificity 44% for advanced CF liver disease) 3
• Splenomegaly (sensitivity 93%, specificity 57% for advanced CF liver disease) 3
• Measure liver span at mid-clavicular line during percussion and palpation 3

Advanced Diagnostic Testing

When initial testing is inconclusive (intermediate sweat chloride values, <2 CF-causing mutations identified), in vivo demonstration of characteristic abnormalities in ion transport across nasal epithelium can serve as diagnostic evidence. 1, 3, 4

These bioassays of CFTR function include:

• Nasal potential difference measurement 4
• Intestinal current measurement 4

Patients with disseminated bronchiectasis, congenital bilateral absence of vas deferens, or acute/recurrent pancreatitis who have some CFTR dysfunction but don't meet full diagnostic criteria are classified as CFTR-related disorder (CFTR-RD). 4

Management During Diagnostic Workup

CF treatment should be initiated immediately in infants with presumptive CF identified through newborn screening, even while diagnostic confirmation is pending, to prevent morbidity and mortality. 6

For patients with intermediate sweat chloride values (30-59 mmol/L on two occasions):

• Perform extended CFTR gene analysis and/or CFTR functional analysis 6
• Measure fecal elastase to evaluate pancreatic function 6
• Obtain respiratory cultures selectively at each visit (at least until age 8 years) 6

Higher-risk patients requiring closer monitoring include those with:

• Initial sweat chloride 40-59 mmol/L 6
• Sweat chloride increasing >5 mmol/L per year 6
• Positive respiratory culture for Pseudomonas aeruginosa 6

Common Diagnostic Pitfalls

The median age of clinical diagnosis based on symptoms alone is 14.5 months (compared to 0.5 months for newborn screening), and delayed diagnosis is associated with >2-fold greater risk of medical complications. 3 Misdiagnoses of food allergies, celiac disease, asthma, or bronchitis are common before CF is recognized. 3

CF should be considered in patients of diverse racial and ethnic backgrounds, not just Caucasians, though prevalence varies (1 in 2500-3300 live births in Caucasian population). 3, 8