Cystic Fibrosis (CF)

Cystic fibrosis (CF) is the most common life-threatening autosomal recessive disorder in the United States, affecting about 1 in 4000 births and occurring at greater rates in some European nations. Cystic fibrosis is a multisystem illness resulting from mutations in the CF transmembrane conductance regulator (CFTR) gene, which encodes an ion channel protein. There have been over 2000 mutations found to date.1 

Newborn Screening and Diagnosis

Meconium ileus, persistent neonatal jaundice, and early respiratory infections are all possible symptoms in newborns with CF. Although clinical signs and symptoms may not develop until later, the median age of diagnosis is 6 to 8 months.2 

Severe bronchiectasis can be seen at the time of diagnosis in cases that remain undetected and untreated in early life.3 

cystic fibrosis CT scan
CT scan of chest showing cystic fibrosis. Credit: Getty Images

The newborn screening (NBS) test is used to make the initial diagnosis of CF in children. If the test results are positive for CF, a conventional sweat test is used to confirm the diagnosis. Lung radiographs are used to monitor the progression of the disease if CF is confirmed.4 

NBS involves a 2-step serial assay. In the first step, serum immunoreactive trypsinogen (IRT) levels are measured in dried blood spots.5 Immunoreactive trypsinogen is a trypsin precursor that accumulates in the blood of persons with impaired release of pancreatic enzymes. Thus, in the majority of infants with CF, raised IRT levels can be detected in the first step of NBS. The second step consists of either another IRT test or a DNA-based test. The sensitivity of a single IRT test or the IRT/IRT combination test for CF is 85% to 90%; however, false-positive rates are high.6 

In the United States, a DNA assay is most commonly used for the second step, which involves analyzing DNA for CFTR gene mutations. The test uses multiple mutation panels to account for the most prevalent CFTR mutations in people with CF. As a result, panel composition is a key concern for NBS programs, particularly in populations with a wide genetic and cultural diversity.5

Diagnosis of Older Children and Adults

Exacerbations of 1 or more symptoms are common in adults with CF.2 The disease typically presents with pulmonary disease, symptoms related to digestion due to pancreatic insufficiency, male infertility as a consequence of absent vas deferens, and increased loss of chloride with sweat.7 

A sweat chloride test is the first step in the diagnostic process. A second sweat chloride test is recommended if the results are normal but the patient is still experiencing symptoms. If the test results are abnormal, DNA testing is recommended. Expanded DNA analysis is recommended if 1 or fewer CFTR mutations are identified. The detection of 2 CF-related mutations, on the other hand, is confirmatory of CF diagnosis.2 Patients with an uncertain CF diagnosis should be evaluated in a specialist CF center. If available, additional electrophysiological investigations (nasal potential difference and intestine short circuit current measurement) should be performed in patients with intermediate sweat test results. The analyses should be carried out in a facility that has vast experience with these techniques.8

Depending on the presenting symptoms, additional investigations may be required. Hyperinflation, bronchiectasis, abscesses, and atelectasis can all be detected on chest radiography. Panopacification of the paranasal sinuses can be seen on sinus radiography.2 

Pulmonary function testing (PFT) is an important technique for assessing and monitoring the disease state and progression in people with CF.  The most common pulmonary function test is spirometry. It measures the volume of air exhaled during a forceful and complete exhalation after a maximal inhalation.2 

Sweat Chloride Test

The sweat chloride test is the primary test for confirmation of CF.9 Cystic fibrosis is likely if the sweat chloride concentration is 60 mmol/L or higher. A sweat chloride concentration of 29 mmol/L or lower is normal and makes the diagnosis of CF extremely unlikely.1 However, because approximately 1% of patients with CF have a normal test result, those with symptoms suggestive of CF and a negative or inconclusive sweat chloride test result (sweat chloride concentration of 30-59 mmol/L) may undergo repeat sweat chloride testing or CFTR genotyping to confirm the diagnosis.10 

Diagnostic Criteria for Cystic Fibrosis

For CF diagnosis, both of the following criteria should be met:

  • Clinical symptoms consistent with CF in at least 1 organ system, or positive NBS or genetic testing for siblings of patients with CF (may also include parent or child)


  • Evidence of CFTR dysfunction (any of the following):
    • Elevated sweat chloride ≥60 mmol/L
    • Presence of 2 disease-causing variants in CFTR, 1 from each parental allele
    • Abnormal nasal potential difference (NPD)

Because the accuracies of sweat chloride and nasal potential difference measurements are operator-dependent, testing should be done in experienced facilities following standard procedures.1 


  1. Farrell PM, White TB, Ren CL, et al. Diagnosis of cystic fibrosis: consensus guidelines from the Cystic Fibrosis Foundation. J Pediatr. 2017;181S:S4-S15.e1. doi:10.1016/j.jpeds.2016.09.064
  2. Yu E, Sharma S. Cystic fibrosis. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2021. Accessed January 10, 2022.
  3. De Boeck K. Cystic fibrosis in the year 2020: a disease with a new face. Acta Paediatr. 2020;109(5):893-899. doi:10.1111/apa.15155
  4. Brown SD, White R, Tobin P. Keep them breathing: cystic fibrosis pathophysiology, diagnosis, and treatment. JAAPA. 2017;30(5):23-27. doi:10.1097/01.JAA.0000515540.36581.92
  5. Pique L, Graham S, Pearl M, Kharrazi M, Schrijver I. Cystic fibrosis newborn screening programs: implications of the CFTR variant spectrum in nonwhite patients. Genet Med. 2017;19(1):36-44. doi:10.1038/gim.2016.48
  6. Farrell MH, Farrell PM. Newborn screening for cystic fibrosis: ensuring more good than harm. J Pediatr. 2003;143(6):707-712. doi:10.1016/j.jpeds.2003.09.022
  7. Padoan R, Quattrucci S, Amato A, et al. The diagnosis of cystic fibrosis in adult age. Data from the Italian registry. Diagnostics (Basel). 2021;11(2):321. doi:10.3390/diagnostics11020321
  8. Castellani C, Duff AJA, Bell SC, et al. ECFS best practice guidelines: the 2018 revision. J Cyst Fibros. 2018;17(2):153-178. doi:10.1016/j.jcf.2018.02.006
  9. Schmidt H, Sharma G. Sweat testing. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2021. Accessed January 10, 2022.
  10. Sosnay PR, Salinas DB, White TB, et al. Applying cystic fibrosis transmembrane conductance regulator genetics and CFTR2 data to facilitate diagnoses. J Pediatr. 2017;181S:S27-S32.e1. doi:10.1016/j.jpeds.2016.09.063

Reviewed by Debjyoti Talukdar, MD, on 1/10/2022.