Cystic fibrosis (CF), a serious autosomal recessive disease, affects approximately one in every 4,000 newborns in the United States but may also be diagnosed later in childhood or in adulthood. Symptoms of CF include lung disease, liver disease, and exocrine and endocrine pancreatic insufficiency. Age of onset, severity of symptoms, and manifestations of CF vary widely. CF is caused by pathogenic variants in the CF transmembrane conductance regulator (CFTR) gene. More than 2,000 CFTR variants have been reported, but most are very rare and of unknown significance, which presents a diagnostic challenge. Sweat chloride testing is the gold standard for diagnostic testing for CF. The immunoreactive trypsinogen (IRT) test is a preliminary assay used for newborn screening. Molecular testing (ie, DNA analysis) can be used for carrier screening, newborn screening, and diagnostic testing.
Quick Answers for Clinicians
Testing recommendations for adult and pediatric populations are the same, regardless of whether the suspicion for cystic fibrosis (CF) arises from newborn screening or symptomatic presentation. Both the Cystic Fibrosis Foundation and European Cystic Fibrosis Society recommend sweat chloride testing. Two elevated (positive) sweat chloride test results on 2 different days are diagnostic for CF; if sweat chloride values are borderline, CFTR genetic testing is recommended. The identification of two severe pathogenic CFTR variants on opposite chromosomes is also diagnostic for CF; however, the absence of a positive genetic result does not exclude CF.
If carrier screening reveals that both members of a couple are cystic fibrosis (CF) carriers, the couple should be offered the option of preimplantation genetic diagnosis or prenatal diagnosis.
CFTR-related metabolic syndrome/CF screen positive, inconclusive diagnosis (CRMS/CFSPID) refers to the combination of a positive newborn screen (high immunoreactive trypsinogen [IRT]), inconclusive sweat chloride test, and inconclusive genetic testing results. Newborns with CRMS/CFSPID may never develop any symptoms of CF but are at risk for CFTR-related disorders such as bilateral absence of the vas deferens, lung disease, and pancreatic insufficiency.
Indications for Testing
- Carrier screening in women who are pregnant or planning a pregnancy
- Carrier screening in individuals with a family history of CF or CFTR-related conditions
- Diagnosis in newborns with a positive newborn screening result
- Diagnosis in adult or pediatric patients with signs or symptoms or a family history of CF
- Confirmation of the causative CFTR gene variants in a known affected individual to determine eligibility for CFTR variant-specific treatment
Laboratory testing is also used to monitor complications in patients with an established diagnosis of CF.
Criteria for Diagnosis
- A positive sweat chloride test result ≥60 mmol/L
- Identification of two CF-causing variants on separate chromosomes and a sweat chloride value of ≥30 mmol/L
- Demonstrated CFTR dysfunction (ie, a sweat chloride test result of ≥60 mmol/L or CF-typical nasal potential difference or intestinal current measurement), regardless of whether or not two molecular pathogenic variants can be identified
Carrier screening for CF is recommended for all women who are pregnant or planning a pregnancy, individuals with a family history of CF, and men with isolated congenital bilateral absence of the vas deferens. A panel test for the 23 most common CF-causing variants is recommended for carrier screening ; each of these variants occurs with a frequency of more than one in 1,000 in a panethnic U.S. population. For more information on the genetics of CF, see the Cystic Fibrosis (CFTR) Expanded Variant Panel Test Fact Sheet.
Screening for CF is recommended for all newborns in the U.S. Screening is performed using a measurement of IRT in blood spots; depending on the results, a reflex test for a panel of common pathogenic CFTR gene variants may be performed. False-negative results occur at an increased rate in infants with meconium ileus.
In individuals with a positive IRT test, positive CFTR genetic test, or suggestive symptoms [see Cystic Fibrosis (CFTR) Expanded Variant Panel Test Fact Sheet], sweat chloride testing is recommended. A sweat chloride test result of ≥60 mmol/L is diagnostic for CF, and no further testing is required. A sweat chloride test result of <30 mmol/L suggests that CF is unlikely, and further testing is not indicated unless clinical suspicion persists. An intermediate sweat chloride test result of 30-59 mmol/L should be clarified with CFTR genetic analysis. CFTR gene sequencing and deletion/duplication analysis should be performed if one or no pathogenic variants are identified on a CF panel of selected variants. If CFTR sequencing and deletion/duplication testing fails to identify two causative variants, functional analysis (nasal potential difference and intestinal current measurement) is recommended. If results are inconclusive, a diagnosis of CFTR-related metabolic syndrome/CF screen positive, inconclusive diagnosis (CRMS/CFSPID) is appropriate.
CF has numerous complications that require careful monitoring.
|Complication||Laboratory Tests||Recommended Frequency|
|Liver disease||Liver enzyme tests (and liver function tests in patients with cirrhosis)||Periodically|
|Exocrine pancreatic insufficiency||Fecal pancreatic elastase-1||Annually during infancy and childhood; testing should also be performed during periods of failure to thrive, weight loss, or diarrhea|
|Pancreatitis||Lipase, amylase tests||On presentation with recurrent unexplained pain and associated nausea/vomiting|
|Diabetes mellitus||Oral glucose tolerance test (confirm with second test)||Annually beginning at 10 yrs of age; more frequently if individual is symptomatic or in cases of pulmonary exacerbation, initiation of glucocorticoids, enteral tube feeding, planning for pregnancy, pregnancy, and planned organ transplantation|
|Nutritional deficiency||Essential fatty acid status (if testing is available), fat-soluble vitamin testing||Annually|
|Allergic bronchopulmonary aspergillosis||Allergy skin testing, serum IgE, Aspergillus-specific IgE, Aspergillus serum precipitins tests||On presentation with symptoms|
|Airway fungal infections||Airway cultures||Every clinic visit|
|Bacterial infection (eg, with Pseudomonas aeruginosa or Staphylococcus aureus)||Cultures||On presentation with acute exacerbation of lung function and to ensure eradication after treatment|
|Nephrolithiasis||Urinalysis||On presentation with signs and symptoms|
|Medication toxicity||According to standard therapeutic drug monitoring protocols||When taking aminoglycosides|
IgE, immunoglobulin E
ARUP Laboratory Tests
Carrier screening for expectant couples and those planning a pregnancy; diagnostic for symptomatic individuals
Polymerase Chain Reaction/Fluorescence Monitoring
For individuals with suspected CF; not indicated for carrier screening
Polymerase Chain Reaction/ Fluorescence Monitoring/Sequencing/Multiplex Ligation-dependent Probe Amplification
Polymerase Chain Reaction/Fluorescence Monitoring/Sequencing
For individuals with suspected CF but without two pathogenic variants detected by the CFTR 165 expanded variant test
Massively Parallel Sequencing/Sequencing
For fetal testing when both parents are known carriers of a variant on the CFTR expanded variant test or if the fetus has an echogenic bowel
Polymerase Chain Reaction/Fluorescence Monitoring
Useful when a pathogenic familial variant identifiable by sequencing is known
Useful when a pathogenic familial variant identifiable by deletion/duplication analysis is known
Use to monitor for liver disease
Use to screen for exocrine pancreatic insufficiency
Use to monitor for pancreatitis
Use to monitor for diabetes mellitus
Use to monitor nutritional status
Quantitative Gas Chromatography/Mass Spectrometry/Stable Isotope Dilution
Use to monitor for allergic bronchopulmonary aspergillosis
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.
Castellani C, Duff AJ, Bell SC, et al. ECFS best practice guidelines: the 2018 revision. J Cyst Fibros. 2018;17(2):153-178.
ACOG Committee on Genetics. ACOG Committee Opinion No. 691: carrier screening for genetic conditions. Obstet Gynecol. 2017;129(3):e41-e55.
Edwards JG, Feldman G, Goldberg J, et al. Expanded carrier screening in reproductive medicine—points to consider: a joint statement of the American College of Medical Genetics and Genomics, American College of Obstetricians and Gynecologists, National Society of Genetic Counselors, Perinatal Quality Foundation, and Society for Maternal-Fetal Medicine. Obstet Gynecol. 2015;125(3):653-662.