Kyle Habet, MD, is a physician at Belize International Institute of Neuroscience where he is a member of a multidisciplinary group of healthcare professionals involved in the care of patients with an array of neurological and psychiatric diseases. He is a published author, researcher and instructor of neuroscience and clinical medicine at Washington University of Health and Science.
In the United States, newborns have been screened for cystic fibrosis (CF) routinely in all 50 states and the District of Columbia since 2010.1 The early detection, intervention, and treatment of CF, including nutrition, may lead to improved outcomes.
Newborn Screening Techniques
Newborn screening (NBS) typically involves a 2-step serial assay. In the first step, the level of serum immunoreactive trypsinogen (IRT) is measured in dried blood spots.1 IRT is a trypsin precursor that accumulates in the blood of individuals in whom the release of pancreatic enzymes is impaired. Therefore, in most infants with CF, elevated IRT levels will be detected by the first step in the screening process. The second step consists of either another IRT test or a DNA-based test. The sensitivity for CF of a single IRT test, or the IRT/IRT combination test, is 85% to 90%; however, false-positive rates are high.2 In the United States, a DNA assay is most widely used for the second step, in which DNA is analyzed for mutations in the CFTR gene. The test uses multiple mutation panels for the most common CFTR mutations in individuals with CF. The panel composition is therefore an important consideration for NBS programs, especially in genetically and ethnically diverse populations.1
Because some NBS programs test only for the p.Phe508del mutation (the most common CFTR mutation in CF), some cases of CF remain undetected; the percentages are higher in non-Caucasian ethnic groups. Other DNA tests used in the United States are the Hologic InPlex CF molecular test, which detects 23 variants; the Luminex xTAG CF39 kit v2, which detects 39 variants; and the Hologix CF InPlex card test, which detects 41 variants. Some states employ full CFTR sequencing in the second step of NBS. It has been proposed that NBS for CF include diverse panels to reduce the number of undetected cases of CF in newborns of non-Caucasian or mixed ethnic origin.1
Newborns with a pathogenic variant of the gene are then referred for a sweat chloride test to confirm the diagnosis.
Sweat Chloride Test
The sweat chloride test is the primary test for confirming CF. Sweating is induced by pilocarpine iontophoresis, and the chloride concentration in the sample is determined. Pilocarpine is applied to an area of the skin to induce sweating. The area is then wrapped in plastic, and the sweat is collected half an hour later.3 Indications for a chloride sweat test include the following4:
- Positive NBS result in an infant weighing more than 2 kg
- Phenotype suggestive of CF
- Symptoms suggestive of CF (eg, meconium ileus) in an infant
- Symptoms suggestive of CF (eg, male infertility, chronic respiratory tract infections, chronic sinusitis) in an older child or adult
- Family history of CF
CF 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.5 However, owing to the fact that approximately 1% of patients with CF have a normal test result, those with symptoms that strongly suggest 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.6
1. 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
2. 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
3. Schmidt H, Sharma G. Sweat Testing – StatPearls – NCBI Bookshelf. StatPearls [Internet]. Updated May 10, 2021. Accessed January 4, 2022.
4. Green A, Kirk J, Guidelines Development Group. Guidelines for the performance of the sweat test for the diagnosis of cystic fibrosis. Ann Clin Biochem. 2007;44(1):25-34. doi:10.1258/000456307779596011
5. Farrell PM, White TB, Ren CL, et al. Diagnosis of cystic fibrosis: consensus guidelines from the Cystic Fibrosis Foundation. J Pediatr. 2017;181:S4-S15.e1. doi:10.1016/j.jpeds.2016.09.064
6. 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 Hasan Avcu, MD, on 1/9/2022.