What is the diagnostic approach for a 1-month-old infant suspected of having cystic fibrosis (CF)?

Diagnosis of Cystic Fibrosis in a 1-Month-Old Infant

In a 1-month-old infant, CF diagnosis requires confirmatory sweat chloride testing (≥60 mmol/L is diagnostic) following a positive newborn screen, combined with CFTR genetic testing to identify disease-causing mutations. 1

Initial Diagnostic Pathway

Newborn Screening Context

• Most 1-month-old infants suspected of CF will have been identified through newborn screening using immunoreactive trypsinogen (IRT), which is the initial screening test but is NOT diagnostic by itself 1
• Elevated IRT can occur due to prematurity, stressful delivery, or CF carrier status, making confirmatory testing essential 1
• The median age of diagnosis through newborn screening is 0.5 months, making this the most common presentation at 1 month of age 2

Sweat Chloride Testing: The Gold Standard

Perform sweat chloride testing bilaterally as soon as the infant meets these criteria: 2, 1

• Weight >2 kg
• At least 36 weeks corrected gestational age
• Ideally after 10 days of age, but must be completed by 4 weeks of age (end of neonatal period)

Interpretation of sweat chloride values: 2, 1

• ≥60 mmol/L = Diagnostic for CF when combined with positive newborn screen, clinical features, or family history
• 30-59 mmol/L = Intermediate/ambiguous range - requires repeat testing and extended CFTR analysis, as infants with CF often initially present with values in this range 2, 1
• <30 mmol/L = CF unlikely but may still be considered if clinical features and CFTR genotyping support CF 2

Critical technical considerations: 2, 1

• Sweat analysis must be performed within a few hours of collection
• Not all infants produce sufficient sweat quantities for reliable testing, particularly those <2 weeks old or <2 kg
• Testing should be performed according to CLSI 2009 Guidelines using pilocarpine iontophoresis 2

Complementary CFTR Genetic Testing

Perform CFTR genetic testing via blood test or cheek swab to identify disease-causing mutations: 1

• Identification of two CF-causing mutations confirms the diagnosis regardless of sweat test results
• If <2 disease-causing variants are identified by newborn screening, CFTR sequencing including intronic regions should be performed 1
• More than 1500 mutations have been identified in the CFTR gene, not all of which result in CF 3

Clinical Evaluation Requirements

CF diagnosis requires BOTH of the following: 1

1. Clinical presentations of disease: chronic respiratory symptoms, pancreatic insufficiency, meconium ileus, or other CF features
2. Evidence of CFTR dysfunction: elevated sweat chloride (≥60 mmol/L) OR two CF-causing mutations OR abnormal nasal epithelial ion transport 2

Common Clinical Presentations at 1 Month

• Meconium ileus (median diagnosis age 0.2 months) 2
• Failure to thrive or poor weight gain
• Steatorrhea (fatty, foul-smelling stools)
• Persistent respiratory symptoms
• Family history of CF in a sibling 2

Management of Indeterminate Results

For Intermediate Sweat Chloride Values (30-59 mmol/L)

Do not delay treatment while establishing diagnosis: 2

• Infants with presumptive CF identified through newborn screening should begin CF treatment immediately
• Repeat sweat chloride testing on two separate occasions 2
• Perform extended CFTR gene analysis 2
• Consider CFTR functional analysis (nasal potential difference or intestinal current measurement) 4

CRMS/CFSPID (Screen-Positive, Inconclusive Diagnosis)

• Some infants will have positive newborn screens but fail to meet full diagnostic criteria 5
• These infants require ongoing monitoring at a CF center but most remain healthy and do not convert to CF diagnosis in childhood 5
• Detailed reassessment should occur in the sixth year of life 5

Critical Pitfalls to Avoid

Never diagnose CF based on genotype analysis alone: 6

• Some CFTR mutations (like R117H with certain intron 8 polymorphisms) may not cause disease despite being identified as "CF mutations"
• Genotype analysis should be an adjunct, not the sole diagnostic criterion 6

Do not wait for adequate sweat production beyond 4 weeks: 2, 1

• While sweat testing can be performed accurately in most infants at 2-3 weeks of age, some infants lack sufficient sweat quantities 2
• If initial testing is inadequate, repeat when the infant is larger, but do not delay clinical management

Recognize that early diagnosis prevents complications: 2

• Diagnosis based on symptoms (median 14.5 months) is associated with >2-fold greater risk of medical complications compared to newborn screening diagnosis (median 0.5 months)
• Delayed diagnosis results in adverse psychosocial effects for families 2

Immediate Next Steps After Diagnosis

Refer immediately to a specialized CF center for: 2

• Comprehensive, multidisciplinary CF care
• Pancreatic enzyme replacement and fat-soluble vitamin supplementation if pancreatic insufficiency is present 2
• Nutritional assessment and support
• Respiratory infection monitoring and treatment protocols
• Family education and psychosocial support 2